Polycyclic derivative, and preparation method therefor and use thereof

Abstract

Disclosed in the present invention are a polycyclic derivative, and a preparation method therefor and the use thereof. In particular, the present invention relates to a compound represented by general formula (I) or a stereoisomer thereof, a preparation method therefor, a pharmaceutical composition comprising the compound, and the use thereof in the preparation of a drug for treating diseases. The compound has a structure as represented by formula (I).

Description

A polycyclic derivative, preparation method and application thereof

[0001] This disclosure requires the following Chinese patent applications filed with the China Patent Office on November 20, 2023, with application number CN202311554182.2 and invention name “A polycyclic derivative, its preparation method and application”, the following Chinese patent applications filed with the China Patent Office on January 4, 2024, with application number CN202410014972.X and invention name “A polycyclic derivative, its preparation method and application”, the following Chinese patent applications filed with the China Patent Office on February 1, 2024, with application number CN202410146490.X and invention name “A polycyclic derivative, its preparation method and application”, the following Chinese patent applications filed with the China Patent Office on March 27, 2024, with application number CN202410363654.4 and invention name The present invention claims priority from the Chinese patent application entitled “A polycyclic derivative, its preparation method and application”, the Chinese patent application filed with the Patent Office of China on June 5, 2024, with application number CN202410726967.1 and invention name “A polycyclic derivative, its preparation method and application”, the Chinese patent application filed with the Patent Office of China on August 9, 2024, with application number CN202411101425.1 and invention name “A polycyclic derivative, its preparation method and application”, and the Chinese patent application filed with the Patent Office of China on November 14, 2024, with application number CN202411631967.X and invention name “A polycyclic derivative, its preparation method and application”, all of which are incorporated by reference into this disclosure. Technical Field

[0002] The present disclosure belongs to the field of medicinal chemistry, and specifically relates to a polycyclic derivative, a preparation method and application thereof. Background Art

[0003] The 2021 WHO global death toll from cardiovascular disease (CVD) totaled 18.6 million, accounting for one-third of all deaths worldwide and the leading cause of death. Furthermore, over three-quarters of CVD deaths occur in low- and middle-income countries. It is estimated that by 2030, there will be over 23 million CVD deaths.

[0004] The primary cause of CVD is dyslipidemia, which can be broadly categorized into four risk factors: elevated LDL-c, decreased HDL-c, elevated triglycerides, and elevated Lp(a). Effective clinical treatments are available for the first three factors. However, there are currently no specific treatments for Lp(a), an independent CVD risk factor. The only FDA-approved treatment for elevated Lp(a), lipoprotein apheresis, is expensive, has a temporary effect, and is not widely applicable. Furthermore, the treatment is cumbersome, requiring repeated treatment every week or two. Furthermore, Lp(a) plasma concentrations are primarily influenced by genetic factors (>90%) and are virtually unaffected by diet or exercise.

[0005] Elevated Lp(a) levels can increase the risk of ASCVD, and Lp(a) ≥50 mg / dL is considered to be associated with a higher risk of ASCVD. Currently, approximately 20% of the population has Lp(a) ≥50 mg / dL, making the development of specific medications to lower Lp(a) to below 50 mg / dL crucial. Summary of the Invention

[0006] The present disclosure aims to provide a compound represented by formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof:

[0007] in,

[0008] M is selected from

[0009] R a1 、R a2 、R a3 and R a5 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl;

[0010] R a4 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl; or R a4 is-L4-T4;

[0011] m1 is selected from 0, 1, 2 or 3;

[0012] L1, L2, L3 and L4 are each independently selected from a bond, -O(CR b1 R b2 ) n1 -、-(CR b3 R b4 ) n2 -、-NR b5 (CR b6 R b7 ) n3 -、-S(CR b8 R b9 ) n4 -、-SO-、-SO2(CR b10 R b11 ) n5 -、-S(=O)(CR b12 R b13 ) n6 -、-CO(CR b14 R b15 ) n7 -, -S(=O)(=NH)-,-N=CR b16 -、-Se(CR b17 R b18 ) n8 -、C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, -OC 3-8 Cycloalkyl-, -O-3-8 membered heterocycloalkyl-, the C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, -OC 3-8 Cycloalkyl-, -O-3-8 membered heterocycloalkyl- optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6substituted by one or more substituents in a haloalkoxy group;

[0013] R b1 、R b2 、R b3 、R b4 、R b5 、R b6 、R b7 、R b8 、R b9 、R b10 、R b11 、R b12 、R b13 、R b14 、R b15 、R b16 、R b17 and R b18 Each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, -L4-T4; or, R on the same carbon atom b1 and R b2 Connect to form C 3-8 Cycloalkyl; or, R on the same carbon atom b3 and R b4 Connect to form C 3-8 Cycloalkyl; or, R on the same carbon atom b6 and R b7 Connect to form C 3-8 Cycloalkyl; or, R on the same carbon atom b8 and R b9 Connect to form C 3-8 Cycloalkyl; or, R on the same carbon atom b10 and R b11 Connect to form C 3-8 Cycloalkyl;

[0014] n1, n2, n3, n4, n5, n6, n7 and n8 are each independently selected from 0, 1, 2, 3 or 4;

[0015] T1, T2, T3 and T4 are each independently selected from the following structural fragments:

[0016] Alternatively, -L3-T3 is hydrogen; or, -L2-T2 is hydrogen;

[0017] M1 is selected from a bond, -(CR 2-1 R 2-2 ) p4 - or NR 2-3 ;

[0018] R2, R 2-1 、R 2-2 、R 2-3 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 haloalkoxy;

[0019] Or, R 2-1 and R 2-2 Connect to form C 3-6 Cycloalkyl, the C 3-6 The cycloalkyl group is optionally substituted with deuterium, halogen, amino, hydroxy, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 substituted by one or more substituents in a haloalkoxy group;

[0020] R3 and R4 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 haloalkoxy;

[0021] Or, R 2-1 Connected with R3 to form C 3-6 Cycloalkyl;

[0022] Alternatively, two R4 on adjacent carbon atoms are linked to form a C 3-6 Cycloalkyl;

[0023] R1, R 1-1 、R 1-2 、R 1-3 、R 1-4 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, -SF5, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 substituted by one or more substituents in a haloalkoxy group;

[0024] Or, R 2-3 and R 1-1 Connected to form a 5-6 membered heteroaryl group;

[0025] Or, R 1-2 and R 1-3 Connect to form C 5-8 Cycloalkenyl, 5-8 membered heterocycloalkenyl, phenyl, 5-6 membered heteroaryl, the C 5-8 Cycloalkenyl, 5-8 membered heterocycloalkenyl, phenyl, 5-6 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 substituted by one or more substituents in a haloalkoxy group;

[0026] Or, R 1-4 and R 1-3 Connect to form C 5-8 Cycloalkenyl, 5-8 membered heterocycloalkenyl, phenyl, 5-6 membered heteroaryl, the C 5-8 Cycloalkenyl, 5-8 membered heterocycloalkenyl, phenyl, 5-6 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 substituted by one or more substituents in a haloalkoxy group;

[0027] Alternatively, R in T1 1-2 and R in T2 1-1 or R 1-2 Connection formation-O(CR c1 R c2 ) p1 -、-(CH2) p2 -、-NR c3 (CH2) p3 -;

[0028] R c1 、R c2 and R c3 Each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl;

[0029] p1, p2 and p3 are each independently selected from 0, 1, 2, 3 or 4;

[0030] R5 is selected from -COOH, -CONHCN, -CONHOH, -CONHSO2CH3, -PO(OH)2, -SO2OH,

[0031] Ring A is selected from C 3-8 Cycloalkyl;

[0032] Ring B is selected from 5-6 membered heterocycloalkyl, 5-10 membered heteroaryl and 5-6 membered heterocycloalkenyl;

[0033] Ring C is selected from C 6-10 Aryl, C 3-8 Cycloalkyl, 5-10 membered heteroaryl, C 3-8 Heterocycloalkenylphenyl, C 3-8 Cycloalkenylphenyl;

[0034] Ring D is selected from C 6-10 Aryl or 5-10 membered heteroaryl;

[0035] p4 is independently selected from 0, 1, 2 or 3;

[0036] n is independently selected from 0 or 1;

[0037] x is independently selected from 0, 1, 2 or 3;

[0038] y is independently selected from 0, 1, 2 or 3;

[0039] z is independently selected from 0, 1, 2 or 3.

[0040] The present disclosure aims to provide a compound represented by formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof:

[0041] in,

[0042] M is selected from

[0043] R a1 、R a2 、R a3 and R a5 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl;

[0044] R a4 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl; or R a4 is-L4-T4;

[0045] m1 is selected from 0, 1, 2 or 3;

[0046] L1, L2, L3 and L4 are each independently selected from a bond, -O(CR b1 R b2 ) n1 -、-(CR b3 R b4 ) n2 -、-NR b5 (CR b6 R b7 ) n3 -、-S(CR b8 R b9 ) n4 -、-SO-、-SO2(CR b10 R b11 ) n5 -、-S(=O)(CR b12 R b13 ) n6 -、-CO(CR b14 R b15 ) n7 -、-S(=O)(=NH)-、C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, -OC 3-8 Cycloalkyl-, -O-3-8 membered heterocycloalkyl-, the C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, -OC 3-8 Cycloalkyl-, -O-3-8 membered heterocycloalkyl- optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 substituted by one or more substituents in a haloalkoxy group;

[0047] R b1 、R b2 、R b3 、R b4 、R b5 、R b6 、R b7 、R b8 、R b9 、R b10 、R b11 、R b12 、R b13 、R b14 and R b15 Each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, -L4-T4; or, R on the same carbon atom b1 and R b2 Connect to form C 3-8 Cycloalkyl; or, R on the same carbon atom b3 and R b4 Connect to form C 3-8 Cycloalkyl; or, R on the same carbon atom b6 and R b7 Connect to form C 3-8 Cycloalkyl; or, R on the same carbon atom b8 and R b9 Connect to form C 3-8 Cycloalkyl; or, R on the same carbon atom b10 and R b11 Connect to form C 3-8 Cycloalkyl;

[0048] n1, n2, n3, n4, n5, n6 and n7 are each independently selected from 0, 1, 2, 3 or 4;

[0049] T1, T2, T3 and T4 are each independently selected from the following structural fragments:

[0050] Alternatively, -L3-T3 is hydrogen; or, -L2-T2 is hydrogen;

[0051] M1 is selected from a bond, -(CR 2-1 R 2-2 ) p4 - or NR 2-3 ;

[0052] R2, R 2-1 、R 2-2 、R 2-3 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 haloalkoxy;

[0053] Or, R 2-1 and R 2-2 Connect to form C 3-6 Cycloalkyl, the C 3-6 The cycloalkyl group is optionally substituted with deuterium, halogen, amino, hydroxy, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 substituted by one or more substituents in a haloalkoxy group;

[0054] R3 and R4 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 haloalkoxy;

[0055] Or, R 2-1 Connected with R3 to form C 3-6 Cycloalkyl;

[0056] Alternatively, two R4 on adjacent carbon atoms are linked to form a C 3-6 Cycloalkyl;

[0057] R1, R 1-1 、R 1-2 、R 1-3 、R 1-4 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, -SF5, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 The haloalkoxy group is optionally substituted with deuterium, halogen, amino, hydroxy, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 substituted by one or more substituents in a haloalkoxy group;

[0058] Or, R 2-3 and R 1-1 Connected to form a 5-6 membered heteroaryl group;

[0059] Or, R 1-2 and R 1-3 Connect to form C 5-8 Cycloalkenyl, 5-8 membered heterocycloalkenyl, phenyl, 5-6 membered heteroaryl, the C 5-8 Cycloalkenyl, 5-8 membered heterocycloalkenyl, phenyl, 5-6 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 substituted by one or more substituents in a haloalkoxy group;

[0060] Or, R 1-4 and R 1-3 Connect to form C 5-8 Cycloalkenyl, 5-8 membered heterocycloalkenyl, phenyl, 5-6 membered heteroaryl, the C 5-8 Cycloalkenyl, 5-8 membered heterocycloalkenyl, phenyl, 5-6 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 substituted by one or more substituents in a haloalkoxy group;

[0061] Alternatively, R in T1 1-2 and R in T2 1-1 or R 1-2 Connection formation-O(CR c1 R c2 ) p1 -、-(CH2) p2 -、-NR c3 (CH2) p3 -;

[0062] R c1 、R c2 and R c3 Each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 haloalkoxy;

[0063] p1, p2 and p3 are each independently selected from 0, 1, 2, 3 or 4;

[0064] R5 is selected from -COOH, -CONHCN, -CONHOH, -CONHSO2CH3, -PO(OH)2, -SO2OH,

[0065] Ring A is selected from C 3-8 Cycloalkyl;

[0066] Ring B is selected from 5-6 membered heterocycloalkyl, 5-10 membered heteroaryl and 5-6 membered heterocycloalkenyl;

[0067] Ring C is selected from C 6-10 Aryl, C 3-8 Cycloalkyl, 5-10 membered heteroaryl, C 3-8 Heterocycloalkenylphenyl;

[0068] Ring D is selected from C 6-10 Aryl or 5-10 membered heteroaryl;

[0069] p4 is independently selected from 0, 1, 2 or 3;

[0070] n is independently selected from 0 or 1;

[0071] x is independently selected from 0, 1, 2 or 3;

[0072] y is independently selected from 0, 1, 2 or 3;

[0073] z is independently selected from 0, 1, 2 or 3.

[0074] The present disclosure aims to provide a compound represented by formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof:

[0075] in,

[0076] M is selected from

[0077] R a1 、R a2 、R a3 and R a5 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl;

[0078] R a4 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl; or R a4 is-L4-T4;

[0079] m1 is selected from 0, 1, 2 or 3;

[0080] L1, L2, L3 and L4 are each independently selected from a bond, -O(CR b1 R b2 ) n1 -、-(CR b3 R b4 ) n2 -、-NR b5 (CR b6 R b7 ) n3 -、-S(CR b8 R b9 ) n4 -、-SO-、-SO2(CR b10 R b11 ) n5 -、-S(=O)(=NH)-、C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, -OC 3-8 Cycloalkyl-, -O-3-8 membered heterocycloalkyl-, the C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, -OC 3-8 Cycloalkyl-, -O-3-8 membered heterocycloalkyl- optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 substituted by one or more substituents in a haloalkoxy group;

[0081] R b1 、Rb2 、R b3 、R b4 、R b5 、R b6 、R b7 、R b8 、R b9 、R b10 and R b11 Each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, -L4-T4; or, R on the same carbon atom b1 and R b2 Connect to form C 3-8 Cycloalkyl; or, R on the same carbon atom b3 and R b4 Connect to form C 3-8 Cycloalkyl; or, R on the same carbon atom b6 and R b7 Connect to form C 3-8 Cycloalkyl; or, R on the same carbon atom b8 and R b9 Connect to form C 3-8 Cycloalkyl; or, R on the same carbon atom b10 and R b11 Connect to form C 3-8 Cycloalkyl;

[0082] n1, n2, n3, n4 and n5 are each independently selected from 0, 1, 2, 3 or 4;

[0083] T1, T2, T3 and T4 are each independently selected from the following structural fragments:

[0084] Alternatively, -L3-T3 is hydrogen; or, -L2-T2 is hydrogen;

[0085] M1 is selected from a bond, -(CR 2-1 R 2-2 ) p4 - or NR 2-3 ;

[0086] R2, R 2-1 、R2-2 、R 2-3 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 haloalkoxy;

[0087] Or, R 2-1 and R 2-2 Connect to form C 3-6 Cycloalkyl, the C 3-6 The cycloalkyl group is optionally substituted with deuterium, halogen, amino, hydroxy, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 substituted by one or more substituents in a haloalkoxy group;

[0088] R3 and R4 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 haloalkoxy;

[0089] Or, R 2-1 Connected with R3 to form C 3-6 Cycloalkyl;

[0090] Alternatively, two R4 on adjacent carbon atoms are linked to form a C 3-6 Cycloalkyl;

[0091] R1, R 1-1 、R 1-2 、R 1-3 、R 1-4 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 The haloalkoxy group is optionally substituted with deuterium, halogen, amino, hydroxy, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 substituted by one or more substituents in a haloalkoxy group;

[0092] Or, R 2-3 and R 1-1 Connected to form a 5-6 membered heteroaryl group;

[0093] Or, R 1-2 and R 1-3 Connect to form C 5-8 Cycloalkenyl, 5-8 membered heterocycloalkenyl, phenyl, 5-6 membered heteroaryl, the C 5-8 Cycloalkenyl, 5-8 membered heterocycloalkenyl, phenyl, 5-6 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 substituted by one or more substituents in a haloalkoxy group;

[0094] Or, R 1-4 and R 1-3 Connect to form C 5-8 Cycloalkenyl, 5-8 membered heterocycloalkenyl, phenyl, 5-6 membered heteroaryl, the C5-8 Cycloalkenyl, 5-8 membered heterocycloalkenyl, phenyl, 5-6 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 substituted by one or more substituents in a haloalkoxy group;

[0095] Alternatively, R in T1 1-2 and R in T2 1-1 or R 1-2 Connection formation-O(CR c1 R c2 ) p1 -、-(CH2) p2 -、-NR c3 (CH2) p3 -;

[0096] R c1 、R c2 and R c3 Each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 haloalkoxy;

[0097] p1, p2 and p3 are each independently selected from 0, 1, 2, 3 or 4;

[0098] R5 is selected from -COOH, -CONHCN, -CONHOH, -CONHSO2CH3, -PO(OH)2, -SO2OH,

[0099] Ring A is selected from C 3-8 Cycloalkyl;

[0100] Ring B is selected from 5-6 membered heterocycloalkyl, 5-10 membered heteroaryl and 5-6 membered heterocycloalkenyl;

[0101] Ring C is selected from C 6-10 Aryl, C 3-8 Cycloalkyl, 5-10 membered heteroaryl, C3-8 Heterocycloalkenylphenyl;

[0102] Ring D is selected from C 6-10 Aryl or 5-10 membered heteroaryl;

[0103] p4 is independently selected from 0, 1, 2 or 3;

[0104] n is independently selected from 0 or 1;

[0105] x is independently selected from 0, 1, 2 or 3;

[0106] y is independently selected from 0, 1, 2 or 3;

[0107] z is independently selected from 0, 1, 2 or 3.

[0108] The present disclosure aims to provide a compound represented by formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof:

[0109] in,

[0110] M is selected from

[0111] R a1 、R a2 、R a3 and R a5 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl;

[0112] R a4 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 3-8Cycloalkyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl; or R a4 is-L4-T4;

[0113] m1 is selected from 0, 1, 2 or 3;

[0114] L1, L2, L3 and L4 are each independently selected from a bond, -O(CR b1 R b2 ) n1 -、-(CR b3 R b4 ) n2 -、-NR b5 (CR b6 R b7 ) n3 -、-S(CR b8 R b9 ) n4 -、-SO-、-SO2(CR b10 R b11 ) n5 -、-S(=O)(=NH)-、C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, -OC 3-8 Cycloalkyl-, -O-3-8 membered heterocycloalkyl-, the C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, -OC 3-8 Cycloalkyl-, -O-3-8 membered heterocycloalkyl- optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 substituted by one or more substituents in a haloalkoxy group;

[0115] R b1 、R b2 、R b3 、R b4 、R b5 、R b6 、R b7 、R b8 、R b9 、R b10 and R b11 Each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, -L4-T4; or, R on the same carbon atom b1 and R b2 Connect to form C 3-8 Cycloalkyl; or, R on the same carbon atom b3 and R b4 Connect to form C 3-8 Cycloalkyl; or, R on the same carbon atom b6 and R b7 Connect to form C 3-8 Cycloalkyl; or, R on the same carbon atom b8 and R b9 Connect to form C 3-8 Cycloalkyl; or, R on the same carbon atom b10 and R b11 Connect to form C 3-8 Cycloalkyl;

[0116] n1, n2, n3, n4 and n5 are each independently selected from 0, 1, 2, 3 or 4;

[0117] T1, T2, T3 and T4 are each independently selected from the following structural fragments:

[0118] Alternatively, -L3-T3 is hydrogen; or, -L2-T2 is hydrogen;

[0119] M1 is selected from a bond, -(CR 2-1 R 2-2 ) p4 - or NR 2-3 ;

[0120] R2, R 2-1 、R 2-2 、R 2-3 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 haloalkoxy;

[0121] Or, R 2-1 and R 2-2 Connect to form C 3-6 Cycloalkyl, the C 3-6 The cycloalkyl group is optionally substituted with deuterium, halogen, amino, hydroxy, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 substituted by one or more substituents in a haloalkoxy group;

[0122] R3 and R4 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 haloalkoxy;

[0123] Or, R 2-1 Connected with R3 to form C 3-6 Cycloalkyl;

[0124] Alternatively, two R4 on adjacent carbon atoms are linked to form a C 3-6 Cycloalkyl;

[0125] R1, R 1-1 、R 1-2 、R 1-3 、R 1-4 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 The haloalkoxy group is optionally substituted with deuterium, halogen, amino, hydroxy, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 substituted by one or more substituents in a haloalkoxy group;

[0126] Or, R 2-3 and R 1-1 Connected to form a 5-6 membered heteroaryl group;

[0127] Or, R 1-2 and R 1-3 Connect to form C 5-8 Cycloalkenyl, 5-8 membered heterocycloalkenyl, phenyl, 5-6 membered heteroaryl, the C 5-8 Cycloalkenyl, 5-8 membered heterocycloalkenyl, phenyl, 5-6 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 substituted by one or more substituents in a haloalkoxy group;

[0128] Or, R 1-4 and R 1-3 Connect to form C 5-8 Cycloalkenyl, 5-8 membered heterocycloalkenyl, phenyl, 5-6 membered heteroaryl, the C 5-8 Cycloalkenyl, 5-8 membered heterocycloalkenyl, phenyl, 5-6 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6substituted by one or more substituents in a haloalkoxy group;

[0129] Alternatively, R in T1 1-2 and R in T2 1-1 or R 1-2 Connection formation-O(CR c1 R c2 ) p1 -、-(CH2) p2 -、-NR c3 (CH2) p3 -;

[0130] R c1 、R c2 and R c3 Each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 haloalkoxy;

[0131] p1, p2 and p3 are each independently selected from 0, 1, 2, 3 or 4;

[0132] R5 is selected from -COOH, -CONHCN, -CONHOH, -CONHSO2CH3, -PO(OH)2, -SO2OH,

[0133] Ring A is selected from C 3-8 Cycloalkyl;

[0134] Ring B is selected from 5-6 membered heterocycloalkyl, 5-10 membered heteroaryl and 5-6 membered heterocycloalkenyl;

[0135] Ring C is selected from C 6-10 Aryl, C 3-8 Cycloalkyl, 5-10 membered heteroaryl;

[0136] Ring D is selected from C 6-10 Aryl or 5-10 membered heteroaryl;

[0137] p4 is independently selected from 0, 1, 2 or 3;

[0138] n is independently selected from 0 or 1;

[0139] x is independently selected from 0, 1, 2 or 3;

[0140] y is independently selected from 0, 1, 2 or 3;

[0141] z is independently selected from 0, 1, 2 or 3.

[0142] The present disclosure aims to provide a compound represented by formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof:

[0143] in,

[0144] M is selected from

[0145] R a1 、R a2 、R a3 and R a5 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl;

[0146] R a4 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl; or R a4 is-L4-T4;

[0147] m1 is selected from 0, 1, 2 or 3;

[0148] L1, L2, L3 and L4 are each independently selected from a bond, -O(CR b1 R b2 ) n1 -、-(CR b3 R b4 ) n2 -、-NR b5 (CR b6R b7 ) n3 -、-S(CR b8 R b9 ) n4 -、-SO-、-SO2(CR b10 R b11 ) n5 -、-S(=O)(=NH)-、C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, -OC 3-8 Cycloalkyl-, -O-3-8 membered heterocycloalkyl-, the C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, -OC 3-8 Cycloalkyl-, -O-3-8 membered heterocycloalkyl- optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 substituted by one or more substituents in a haloalkoxy group;

[0149] R b1 、R b2 、R b3 、R b4 、R b5 、R b6 、R b7 、R b8 、R b9 、R b10 and R b11 Each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, -L4-T4; or, R on the same carbon atom b1 and R b2 Connect to form C 3-8 Cycloalkyl; or, R on the same carbon atom b3 and R b4 Connect to form C 3-8 Cycloalkyl; or, R on the same carbon atomb6 and R b7 Connect to form C 3-8 Cycloalkyl; or, R on the same carbon atom b8 and R b9 Connect to form C 3-8 Cycloalkyl; or, R on the same carbon atom b10 and R b11 Connect to form C 3-8 Cycloalkyl;

[0150] n1, n2, n3, n4 and n5 are each independently selected from 0, 1, 2, 3 or 4;

[0151] T1, T2, T3 and T4 are each independently selected from the following structural fragments:

[0152] Alternatively, -L3-T3 is hydrogen; or, -L2-T2 is hydrogen;

[0153] M1 is selected from a bond, -(CR 2-1 R 2-2 ) p4 - or NR 2-3 ;

[0154] R2, R 2-1 、R 2-2 、R 2-3 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 haloalkoxy;

[0155] Or, R 2-1 and R 2-2 Connect to form C 3-6 Cycloalkyl, the C 3-6 The cycloalkyl group is optionally substituted with deuterium, halogen, amino, hydroxy, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6substituted by one or more substituents in a haloalkoxy group;

[0156] R3 and R4 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 haloalkoxy;

[0157] Or, R 2-1 Connected with R3 to form C 3-6 Cycloalkyl;

[0158] Alternatively, two R4 on adjacent carbon atoms are linked to form a C 3-6 Cycloalkyl;

[0159] R1, R 1-1 、R 1-2 、R 1-3 、R 1-4 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 The haloalkoxy group is optionally substituted with deuterium, halogen, amino, hydroxy, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6substituted by one or more substituents in a haloalkoxy group;

[0160] Or, R 2-3 and R 1-1 Connected to form a 5-6 membered heteroaryl group;

[0161] Or, R 1-2 and R 1-3 Connect to form C 5-8 Cycloalkenyl, 5-8 membered heterocycloalkenyl, phenyl, 5-6 membered heteroaryl, the C 5-8 Cycloalkenyl, 5-8 membered heterocycloalkenyl, phenyl, 5-6 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 substituted by one or more substituents in a haloalkoxy group;

[0162] Or, R 1-4 and R 1-3 Connect to form C 5-8 Cycloalkenyl, 5-8 membered heterocycloalkenyl, phenyl, 5-6 membered heteroaryl, the C 5-8 Cycloalkenyl, 5-8 membered heterocycloalkenyl, phenyl, 5-6 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 substituted by one or more substituents in a haloalkoxy group;

[0163] Alternatively, R in T1 1-2 and R in T2 1-1 or R 1-2 Connection formation-O(CR c1 R c2 ) p1 -、-(CH2) p2 -、-NR c3 (CH2) p3 -;

[0164] R c1 、R c2and R c3 Each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 haloalkoxy;

[0165] p1, p2 and p3 are each independently selected from 0, 1, 2, 3 or 4;

[0166] R5 is selected from -COOH, -CONHCN, -CONHOH, -CONHSO2CH3, -PO(OH)2, -SO2OH,

[0167] Ring A is selected from C 3-8 Cycloalkyl;

[0168] Ring B is selected from 5-6 membered heterocycloalkyl, 5-10 membered heteroaryl and 5-6 membered heterocycloalkenyl;

[0169] Ring C is selected from C 6-10 Aryl, C 3-8 Cycloalkyl, 5-10 membered heteroaryl;

[0170] Ring D is selected from C 6-10 Aryl or 5-10 membered heteroaryl;

[0171] p4 is independently selected from 0, 1, 2 or 3;

[0172] n is independently selected from 0 or 1;

[0173] x is independently selected from 0, 1, 2 or 3;

[0174] y is independently selected from 0, 1, 2 or 3;

[0175] z is independently selected from 0, 1, 2 or 3.

[0176] In certain embodiments of the present disclosure, -L3-T3 is hydrogen; the definitions of other groups are as defined in any technical solution herein.

[0177] In certain embodiments of the present disclosure, -L3-T3 is hydrogen, and -L2-T2 is hydrogen; the definitions of other groups are as defined in any technical solution herein.

[0178] In certain embodiments of the present disclosure, M is selected from

[0179] R a1 , Ra2 and R a3 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl;

[0180] R a4 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl; or R a4 is-L4-T4;

[0181] The definitions of other groups are as defined in any technical solution herein.

[0182] In certain embodiments of the present disclosure, M is selected from The definitions of other groups are as defined in any technical solution herein.

[0183] In certain embodiments of the present disclosure, R a1 、R a2 and R a3 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy, C 3-6Cycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl; other groups are defined as in any technical solution herein.

[0184] In certain embodiments of the present disclosure, R a4 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl; other groups are defined as in any technical solution herein.

[0185] In certain embodiments of the present disclosure, R a4 The definitions of other groups are as defined in any technical solution herein.

[0186] In certain embodiments of the present disclosure, M is selected from The definitions of other groups are as defined in any technical solution herein.

[0187] In certain embodiments of the present disclosure, M is selected from The definitions of other groups are as defined in any technical solution herein.

[0188] In certain embodiments of the present disclosure, M is selected from The definitions of other groups are as defined in any technical solution herein.

[0189] In certain embodiments of the present disclosure, M is selected from The definitions of other groups are as defined in any technical solution herein.

[0190] In certain embodiments of the present disclosure, R b1 、R b2 、R b3 、R b4 、R b5 、R b6 、R b7 、R b8 、R b9 、R b10 、R b11 、R b12 、R b13 、R b14、R b15 、R b16 、R b17 and R b18 Each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy, C 3-6 Cycloalkyl; or, R on the same carbon atom b1 and R b2 Connect to form C 3-6 Cycloalkyl; or, R on the same carbon atom b3 and R b4 Connect to form C 3-6 Cycloalkyl; or, R on the same carbon atom b6 and R b7 Connect to form C 3-6 Cycloalkyl; or, R on the same carbon atom b8 and R b9 Connect to form C 3-6 Cycloalkyl; or, R on the same carbon atom b10 and R b11 Connect to form C 3-6 The definitions of other groups are as defined in any technical solution herein.

[0191] In certain embodiments of the present disclosure, R b1 、R b2 、R b3 、R b4 、R b5 、R b6 、R b7 、R b8 、R b9 、R b10 、R b11 、R b12 、R b13 、R b14 and R b15 Each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C1-3 Alkylthio, C 1-3 Halogenated alkoxy, C 3-6 Cycloalkyl; or, R on the same carbon atom b1 and R b2 Connect to form C 3-6 Cycloalkyl; or, R on the same carbon atom b3 and R b4 Connect to form C 3-6 Cycloalkyl; or, R on the same carbon atom b6 and R b7 Connect to form C 3-6 Cycloalkyl; or, R on the same carbon atom b8 and R b9 Connect to form C 3-6 Cycloalkyl; or, R on the same carbon atom b10 and R b11 Connect to form C 3-6 The definitions of other groups are as defined in any technical solution herein.

[0192] In certain embodiments of the present disclosure, R b1 、R b2 、R b3 、R b4 、R b5 、R b6 、R b7 、R b8 、R b9 、R b10 and R b11 Each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy, C 3-6 Cycloalkyl; or, R on the same carbon atom b1 and R b2 Connect to form C 3-6 Cycloalkyl; or, R on the same carbon atom b3 and R b4 Connect to form C 3-6 Cycloalkyl; or, R on the same carbon atom b6 and R b7 Connect to form C 3-6 Cycloalkyl; or, R on the same carbon atom b8 and Rb9 Connect to form C 3-6 Cycloalkyl; or, R on the same carbon atom b10 and R b11 Connect to form C 3-6 The definitions of other groups are as defined in any technical solution herein.

[0193] In certain embodiments of the present disclosure, L1, L2, L3 and L4 are each independently selected from -CH2-, a bond, -CH2CH2-, *-N(CH3)CH2CH2-, *-NHCH2CH2-, -NH-, *-NHCH2-, *-N(CH3)CH2-, -O-, -S-, -SO-, -SO2-, -S(=O)(=NH)-, *-OCH2-, *-CH2O-, *-CH2NH-, *-SCH2-, *-SO2CH2-, *-OC(CH3)2-, Wherein the * end is connected to M; the definitions of other groups are as defined in any technical solution of this invention.

[0194] In certain embodiments of the present disclosure, L1, L2, L3 and L4 are each independently selected from Wherein the * end is connected to M; the definitions of other groups are as defined in any technical solution of this invention.

[0195] In certain embodiments of the present disclosure, L1, L2, L3 and L4 are each independently selected from *-OCH2CH2-, *-N(CH2-T4)CH2-, *-S(=O)CH2-, *-C(=O)CH2-, *-C(=O)-, Wherein the * end is connected to M; the definitions of other groups are as defined in any technical solution of this invention.

[0196] In certain embodiments of the present disclosure, L1, L2, L3 and L4 are each independently selected from *-OCD2-, *-CD2-, wherein the * end is connected to M; the definitions of other groups are as defined in any technical solution herein.

[0197] In certain embodiments of the present disclosure, L1, L2, L3 and L4 are each independently selected from -CF2-, *-N=CH-, *-SeCH2-, -Se-, *-CH2CH2Se-, wherein the * end is connected to M; the definitions of other groups are as defined in any technical solution herein.

[0198] In certain embodiments of the present disclosure, L1 and L2 are selected from -CH2-; L3 is selected from *-OCH2-; wherein the * end is connected to M; and the definitions of other groups are as defined in any technical solution herein.

[0199] In certain embodiments of the present disclosure, R2, R 2-1 、R 2-2 、R 2-3 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 The definitions of other groups are as defined in any technical solution herein.

[0200] In certain embodiments of the present disclosure, R 2-1 and R 2-2 are each independently selected from hydrogen or fluorine; the definitions of other groups are as defined in any technical solution herein.

[0201] In certain embodiments of the present disclosure, R 2-3 R2 is selected from hydrogen; other groups are defined as defined in any technical solution herein.

[0202] In certain embodiments of the present disclosure, R 2-1 and R 2-2 Connect to form cyclopropyl, The definitions of other groups are as defined in any technical solution herein.

[0203] In certain embodiments of the present disclosure, R 2-3 and R 1-1 Connection formation The definitions of other groups are as defined in any technical solution herein.

[0204] In certain embodiments of the present disclosure, R1, R 1-1 、R 1-2 、R 1-3 、R 1-4 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl are optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 The haloalkoxy group is substituted by one or more substituents; the definitions of other groups are as defined in any technical solution herein.

[0205] In certain embodiments of the present disclosure, R1, R 1-1 、R 1-2 、R 1-3 、R 1-4 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy, the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 The haloalkoxy group is optionally substituted with deuterium, halogen, amino, hydroxy, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 The haloalkoxy group is substituted by one or more substituents; the definitions of other groups are as defined in any technical solution herein.

[0206] In certain embodiments of the present disclosure, R1, R 1-1 are each independently selected from hydrogen or methyl; the definitions of other groups are as defined in any technical solution herein.

[0207] In certain embodiments of the present disclosure, R1, R 1-1 Each is independently selected from methoxy or deuterium; the definitions of other groups are as defined in any technical solution herein.

[0208] In certain embodiments of the present disclosure, R 1-2 、R 1-3 、R 1-4 Each is independently selected from hydrogen, methyl, methoxy, chlorine, fluorine, -NHCH3; the definitions of other groups are as defined in any technical solution herein.

[0209] In certain embodiments of the present disclosure, R 1-2 、R 1-3 、R 1-4 Each is independently selected from bromine, -CH2OH, -CH2OCH3; the definitions of other groups are as defined in any technical solution herein.

[0210] In certain embodiments of the present disclosure, R 1-2 、R 1-3 、R 1-4 are each independently selected from deuterium; the definitions of other groups are as defined in any technical solution herein.

[0211] In certain embodiments of the present disclosure, R 1-2 and R 1-3 Connect to form C 5-8 Cycloalkenyl, 5-8 membered heterocycloalkenyl, phenyl, 5-6 membered heteroaryl, the C 5-8 Cycloalkenyl, 5-8 membered heterocycloalkenyl, phenyl, 5-6 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3Alkoxy, C 1-3 Alkylthio, C 1-3 The haloalkoxy group is substituted by one or more substituents; the definitions of other groups are as defined in any technical solution herein.

[0212] In certain embodiments of the present disclosure, preferably, R 1-2 and R 1-3 Connection formation The definitions of other groups are as defined in any technical solution herein.

[0213] In certain embodiments of the present disclosure, preferably, R 1-2 and R 1-3 Connection formation The definitions of other groups are as defined in any technical solution herein.

[0214] In certain embodiments of the present disclosure, preferably, R 1-2 and R 1-3 Connection formation The definitions of other groups are as defined in any technical solution herein.

[0215] In certain embodiments of the present disclosure, R 1-4 and R 1-3 Connect to form C 5-8 Cycloalkenyl, 5-8 membered heterocycloalkenyl, phenyl, 5-6 membered heteroaryl, the C 5-8 Cycloalkenyl, 5-8 membered heterocycloalkenyl, phenyl, 5-6 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 The haloalkoxy group is substituted by one or more substituents; the definitions of other groups are as defined in any technical solution herein.

[0216] In certain embodiments of the present disclosure, R 1-4 and R 1-3 Connection formation The definitions of other groups are as defined in any technical solution herein.

[0217] In certain embodiments of the present disclosure, R1, R 1-1 are each independently selected from fluorine; the definitions of other groups are as defined in any technical solution herein.

[0218] In certain embodiments of the present disclosure, R1, R 1-1 are each independently selected from chlorine; the definitions of other groups are as defined in any technical solution herein.

[0219] In certain embodiments of the present disclosure, R 1-2 、R 1-3 、R 1-4 Each is independently selected from -SF5; the definitions of other groups are as defined in any technical solution herein.

[0220] In certain embodiments of the present disclosure, R 1-2 、R 1-3 、R 1-4 Each independently selected from -OCH(CH3)2, -NHCH(CH3)2, The definitions of other groups are as defined in any technical solution herein.

[0221] In certain embodiments of the present disclosure, R3 and R4 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 The definitions of other groups are as defined in any technical solution herein.

[0222] In certain embodiments of the present disclosure, R3 is independently selected from hydrogen; the definitions of other groups are as defined in any of the technical solutions herein.

[0223] In certain embodiments of the present disclosure, R4 is independently selected from hydrogen or methyl; the definitions of other groups are as defined in any technical solution herein.

[0224] In certain embodiments of the present disclosure, R 2-1 and R3 are connected to form a cyclopropyl group; the definitions of other groups are as defined in any technical solution of this invention.

[0225] In certain embodiments of the present disclosure, two R4 on adjacent carbon atoms are linked to form a cyclopropyl group; the definitions of other groups are as defined in any technical solution herein.

[0226] In certain embodiments of the present disclosure, R c1 、R c2 and R c3Each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy, C 3-6 The definitions of other groups are as defined in any technical solution herein.

[0227] In certain embodiments of the present disclosure, R c1 、R c2 and R c3 Each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 The definitions of other groups are as defined in any technical solution herein.

[0228] In certain embodiments of the present disclosure, R in T1 1-2 and R in T2 1-1 or R 1-2 Connected to form -CH2CH2-, -CH2-, -NH-, -O-, -NHCH2-, -N(CH3)-; the definitions of other groups are as defined in any technical solution herein.

[0229] In certain embodiments of the present disclosure, R in T1 1-2 and R in T2 1-1 or R 1-2 Connect to form -N(CH2CH3)-, The definitions of other groups are as defined in any technical solution herein.

[0230] In certain embodiments of the present disclosure, Ring A is selected from C 4-6 The definitions of other groups are as defined in any technical solution herein.

[0231] In certain embodiments of the present disclosure, Ring A is selected from cyclobutyl; the definitions of other groups are as defined in any of the technical schemes herein.

[0232] In certain embodiments of the present disclosure, Ring A is selected from The definitions of other groups are as defined in any technical solution herein.

[0233] In certain embodiments of the present disclosure, Ring B is selected from The definitions of other groups are as defined in any technical solution herein.

[0234] In certain embodiments of the present disclosure, Ring B is selected from The definitions of other groups are as defined in any technical solution herein.

[0235] In certain embodiments of the present disclosure, ring C is selected from phenyl, The definitions of other groups are as defined in any technical solution herein.

[0236] In certain embodiments of the present disclosure, ring C is selected from phenyl, Wherein the * end is connected to L1, L2, L3 or L4; the definitions of other groups are as defined in any technical solution of this invention.

[0237] In certain embodiments of the present disclosure, ring C is selected from Wherein the * end is connected to L1, L2, L3 or L4; the definitions of other groups are as defined in any technical solution of this invention.

[0238] In certain embodiments of the present disclosure, ring C is selected from Wherein the * end is connected to L1, L2, L3 or L4; the definitions of other groups are as defined in any technical solution of this invention.

[0239] In certain embodiments of the present disclosure, ring D is selected from phenyl or 5-10 membered heteroaryl; the definitions of other groups are as defined in any of the technical solutions herein.

[0240] In certain embodiments of the present disclosure, ring D is selected from phenyl or The definitions of other groups are as defined in any technical solution herein.

[0241] In certain embodiments of the present disclosure, T1 and T2 are the same; the definitions of other groups are as defined in any technical solution herein.

[0242] In certain embodiments of the present disclosure, T1, T2, and T3 are the same; the definitions of other groups are as defined in any technical solution herein.

[0243] In certain embodiments of the present disclosure, L1 and L2 are the same; the definitions of other groups are as defined in any technical solution herein.

[0244] In certain embodiments of the present disclosure, L1, L2 and L3 are the same; the definitions of other groups are as defined in any technical solution herein.

[0245] In certain embodiments of the present disclosure, T3 is Among them, R 1-2 and R 1-3 connected to form a C5-C6 heterocycloalkenyl group; preferably, the heteroatom in the C5-C6 heterocycloalkenyl group is oxygen; more preferably, the number of heteroatoms in the C5-C6 heterocycloalkenyl group is 2; the definitions of other groups are as defined in any technical solution herein.

[0246] In certain embodiments of the present disclosure, the structural fragment for T1 and T2 are T3 is The definitions of other groups are as defined in any technical solution herein.

[0247] In certain embodiments of the present disclosure, the structural fragment for T1 and T2 are T3 is Preferably, R 1-1 、R 1-2 、R 1-3 、R 1-4 Each is independently selected from hydrogen; preferably, M1 is selected from -CH2-; preferably, R3 is selected from hydrogen; preferably, R4 is selected from hydrogen; preferably, n is 1; the definitions of other groups are as defined in any technical solution herein.

[0248] In certain embodiments of the present disclosure, the structural fragment for T1 and T2 are The definitions of other groups are as defined in any technical solution herein.

[0249] In certain embodiments of the present disclosure, the structural fragment for T1 and T2 are The definitions of other groups are as defined in any technical solution herein.

[0250] In certain embodiments of the present disclosure, the structural fragment for Preferably, R 1-1 、R 1-3 、R1-4 are each independently selected from hydrogen; preferably, M1 is selected from -CH2-; preferably, R3 is selected from hydrogen; preferably, R4 is selected from hydrogen; preferably, n is 1;

[0251] T1 and T2 are Preferably, R 1-4 is selected from methoxy; preferably, R 1-1 、R 1-2 、R 1-3 are each independently selected from hydrogen; preferably, M1 is selected from -CH2-; preferably, R3 is selected from hydrogen; preferably, R4 is selected from hydrogen; preferably, n is 1;

[0252] The definitions of other groups are as defined in any technical solution herein.

[0253] In certain embodiments of the present disclosure, the structural fragment for T1 and T2 are The definitions of other groups are as defined in any technical solution herein.

[0254] In certain embodiments of the present disclosure, the structural fragment for T1 and T2 are The definitions of other groups are as defined in any technical solution herein.

[0255] The present disclosure also provides a pharmaceutical composition comprising the compound, stereoisomer or pharmaceutically acceptable salt thereof of the present disclosure and a pharmaceutically acceptable carrier.

[0256] In certain embodiments of the present disclosure, in the pharmaceutical composition, the content of the compound, stereoisomer or pharmaceutically acceptable salt thereof is selected from 0.1 mg to 1000 mg.

[0257] In certain embodiments of the present disclosure, in the pharmaceutical composition, the pharmaceutically acceptable carrier includes one or more of a filler, a disintegrant, a binder, a glidant, and a lubricant.

[0258] The present disclosure also provides a use of the above-mentioned compound, stereoisomer or pharmaceutically acceptable salt thereof or the above-mentioned pharmaceutical composition in the preparation of a drug for treating diseases associated with elevated Lp(a) plasma levels.

[0259] In certain embodiments of the present disclosure, the disease is selected from cardiovascular disease, preferably atherosclerotic cardiovascular disease (ASCVD) or hyperlipoproteinaemia (i.e., hyperlipoprotein(a)emia). The atherosclerotic cardiovascular disease is preferably coronary heart disease, coronary atherosclerosis, ischemic stroke, myocardial infarction, atherosclerotic renal vascular disease, or non-infarct coronary artery disease.

[0260] The present disclosure also provides a method for treating a disease associated with elevated Lp(a) plasma levels in a human, wherein the method comprises administering to a human in need thereof an effective preventive or therapeutic amount of the above-mentioned compound, stereoisomer or pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition.

[0261] In certain embodiments of the present disclosure, the disease is selected from cardiovascular disease, preferably atherosclerotic cardiovascular disease (ASCVD) or hyperlipoprotein(a)emia. The atherosclerotic cardiovascular disease is preferably coronary heart disease, coronary atherosclerosis, ischemic stroke, myocardial infarction, atherosclerotic renal vascular disease, or non-infarct coronary artery disease.

[0262] Technical Effects

[0263] The compounds disclosed herein have a significant inhibitory effect on Lp(a) assembly and are highly selective for plasminogen.

[0264] Description and Definition

[0265] Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered ambiguous or unclear without a specific definition, but should be understood according to its ordinary meaning.

[0266] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0267] The term "pharmaceutically acceptable salt" refers to a derivative of a compound of the present invention prepared with a relatively non-toxic acid or base. These salts can be prepared during compound synthesis, separation, and purification, or can be prepared by reacting the purified free form of the compound with a suitable acid or base. When the compound contains a relatively acidic functional group (e.g., -COOH, -OH, -SO3H, etc.), it reacts with an appropriate inorganic or organic cation (base) to form a base addition salt, including salts formed with alkali metals or alkaline earth metals, ammonium salts formed with amines or their derivatives, salts formed with amino acids, etc. When the compound contains a relatively basic functional group (e.g., -NH2, etc.), it reacts with an appropriate inorganic or organic anion (acid) to form an acid addition salt, including salts formed with an inorganic acid or organic acid (e.g., carboxylic acid, etc.).

[0268] The term "pharmaceutically acceptable carrier" refers to a medium generally accepted in the art for delivering biologically active agents to animals, particularly mammals, and includes adjuvants, excipients, or vehicles, such as diluents, preservatives, fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungal agents, lubricants, and dispersants, depending on the mode of administration and the nature of the dosage form. Pharmaceutically acceptable carriers are formulated within the purview of those skilled in the art based on a wide range of factors. These include, but are not limited to, the type and nature of the active agent being formulated, the subject to whom the composition containing the agent is to be administered, the intended route of administration of the composition, and the intended therapeutic indication. Pharmaceutically acceptable carriers include both aqueous and non-aqueous media, as well as a variety of solid and semisolid dosage forms. In addition to the active agent, such carriers include a variety of different ingredients and additives, and the inclusion of such additional ingredients in a formulation for various reasons (e.g., to stabilize the active agent, as a binder, etc.) is well known to those skilled in the art.

[0269] The term "effective prophylactic or therapeutic amount" refers to a sufficient amount of a compound of the present disclosure, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof to treat a disorder at a reasonable benefit / risk ratio applicable to any medical treatment and / or prevention. However, it should be recognized that the total daily dosage of the compound of the present disclosure, its stereoisomers, or pharmaceutically acceptable salts thereof, and compositions must be determined by the attending physician within the scope of sound medical judgment. For any particular patient, the specific therapeutically effective dosage level must be determined based on a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the patient's age, weight, general health, sex, and diet; the administration time, route of administration, and excretion rate of the specific compound employed; the duration of treatment; drugs used in combination with or concurrently with the specific compound employed; and similar factors well known in the medical field.

[0270] The "stereoisomers" described in the present disclosure include atropisomers, cis-trans isomers, enantiomers, diastereomers, and racemic mixtures and other mixtures thereof, all of which fall within the scope of the present disclosure. The term "enantiomer" refers to stereoisomers that are mirror images of each other. The term "diastereomer" refers to stereoisomers whose molecules have two or more chiral centers and are not mirror images of each other. The term "cis-trans isomer" refers to different spatial configurations that exist in a molecule where double bonds or single bonds of ring carbon atoms cannot rotate freely. The term "atropisomer" refers to stereoisomers that can be separated because single bond rotation is hindered or rotates very slowly. Stereoisomers of the compounds disclosed herein can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. For example, one enantiomer of a compound disclosed herein can be prepared by asymmetric catalysis or chiral auxiliary derivatization; or by chiral resolution techniques to obtain a compound of a single stereoconfiguration from a mixture; or directly prepared using chiral starting materials. The separation of optically pure compounds in the present disclosure is usually accomplished using preparative chromatography, employing a chiral chromatographic column to achieve the purpose of separating chiral compounds.

[0271] The absolute stereoconfiguration of a compound can be confirmed by conventional techniques in the art. For example, single crystal X-ray diffraction can be used, or the chiral structure of the starting materials and the reaction mechanism of asymmetric synthesis can be used to confirm the absolute configuration of the compound. Alternatively, after resolution, the stereoconfiguration can be determined by comparison with products with a known absolute configuration. Compounds labeled "absolute configuration unknown / undetermined" herein are typically resolved from racemic compounds into individual isomers by chiral preparative SFC, followed by characterization and testing.

[0272] The term "optionally" means that it may be substituted or not substituted. Unless otherwise specified, the type and number of substituents can be arbitrary based on chemical feasibility. For example, the term "optionally substituted with one or more R1" means that it may be substituted with one or more R1 or not substituted with R1.

[0273] When any variable (e.g., R1) occurs more than once in a compound's composition or structure, its definition on each occurrence is independent. For example, It means that the phenyl group is substituted by y R1s, and each R1 has independent options.

[0274] When a substituent's bond crosses two atoms in a ring, the substituent may be bonded to any atom in the ring. It means that the substituent R1 can be substituted at any position on the phenyl group.

[0275] When a substituent is listed without specifying the atom through which it is bonded to a compound included in the general chemical formula but not specifically mentioned, the substituent may be bonded through any atom thereof. For example, pyrimidine as a substituent means that any carbon atom or nitrogen atom on the pyrimidine ring is bonded to the substituted group; when a substituent appears in the structure , it indicates that the atom is a bonding atom, for example It indicates that the C atoms on the pyrimidine ring are bonding atoms.

[0276] Unless otherwise specified, the term "alkyl" refers to a group derived from a branched or straight chain saturated aliphatic alkane having the specified number of carbon atoms by removing one hydrogen. For example, "C 1-6 "Alkyl" refers to C1, C2, C3, C4, C5, C6 alkyl, "C 1-6 Alkyl", "C 1-3 "alkyl"; specific examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, sec-butyl, 2-methylbutyl, 1,1-dimethylbutyl, etc.

[0277] Unless otherwise specified, the term "alkenyl" refers to a radical derived from a straight-chain or branched alkene (containing at least one carbon-carbon double bond) by removing a hydrogen atom, including "C 2-6 Alkenyl", "C 2-5 Alkenyl", "C 2-4 Alkenyl", "C 2-3 "Alkenyl", specific examples include but are not limited to: -CH=CH2, -CH=CHCH3, -C(CH2)=CH2, -CH=CHCH2CH3, -CH2CH=CHCH3, etc.

[0278] Unless otherwise specified, the term "alkynyl" refers to a radical derived from a straight-chain or branched alkyne (containing at least one carbon-carbon triple bond) by removing a hydrogen atom, including "C 2-6 Alkynyl", "C 2-4 Alkynyl", "C 2-3 Specific examples include, but are not limited to: -C≡CH, -C≡CHCH3, CH≡CHCH2-, CH≡CC≡C-, etc.

[0279] Unless otherwise specified, the term "alkoxy" refers to an alkyl group as defined herein attached to another group through an oxygen atom, i.e., "alkyl-O-". 1-6 Alkoxy" (structure is C 1-6 Alkyl-O-), "C 1-3 "alkoxy", specific examples include but are not limited to methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, etc.; preferably, the "alkoxy" described in the present disclosure is preferably C1-3 Alkoxy.

[0280] Unless otherwise specified, the term "halogen" means a fluorine, chlorine, bromine or iodine atom.

[0281] Unless otherwise specified, the term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by a halogen atom. 1-6 Halogenated alkyl, more preferably C 1-3 Examples of haloalkyl include, but are not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, tribromomethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, and the like. Alkyl is as defined above.

[0282] Unless otherwise specified, the term "hydroxyalkyl" refers to a group derived from an alkyl group in which one or more hydrogen atoms are replaced by a hydroxyl group. The "hydroxyalkyl" described in the present disclosure includes "C 1-6 Hydroxyalkyl", "C 1-3 Specific examples include, but are not limited to, -CH2OH, -CH2CH2OH, -CH(OH)CH3, -CH2CH2CH2OH, wait.

[0283] Unless otherwise specified, the term "alkylthio" refers to an -S-alkyl group in which alkyl is as previously defined.

[0284] Unless otherwise specified, the term "haloalkoxy" refers to a group in which one or more hydrogen atoms in an alkoxy group are replaced by halogen. Preferably, the "haloalkoxy" described in the present disclosure is preferably a "haloC 1-6 Alkoxy", "halogenated C 1-3 Alkoxy". Specific examples of the present disclosure include: fluoromethoxy (including monofluoromethoxy, difluoromethoxy, trifluoromethoxy), -OCH2CF3, -OCHFCH3, etc. Alkoxy is as defined above.

[0285] Unless otherwise specified, the term "ring" refers to saturated, partially saturated, or unsaturated monocyclic and polycyclic rings, and "polycyclic" includes spirocyclic, fused, or bridged rings. A group derived from a ring by removing a hydrogen atom is called a "cyclic group," which includes monovalent rings, divalent rings (commonly referred to as subrings), trivalent rings, and tetravalent rings, with the specific valence depending on the number of substituents attached to the ring. The description of "cyclic groups" in this disclosure does not distinguish between ring valences.

[0286] Unless otherwise specified, the term "hetero" refers to substituted or unsubstituted heteroatoms and oxidized forms of heteroatoms (also known as heteroatomic groups), wherein the heteroatoms are generally selected from N, O, and S, and the oxidized forms generally include NO, SO, S(O)2, and P(O). The nitrogen atom may be substituted, i.e., NR (R is H or other substituents defined herein); the number of atoms in the ring is generally defined as the number of ring members, for example, "3-6 membered heterocycloalkyl" refers to a ring of 3-6 atoms arranged around, each ring optionally containing 1 to 3 heteroatoms, i.e., N, O, CO, S, NO, SO, S(O)2 or NR, each ring optionally substituted by an R group, where R is a group defined herein.

[0287] Unless otherwise specified, the term "cycloalkyl" refers to a saturated cyclic alkyl derived from a cycloalkane by removing a hydrogen atom, including monocyclic or polycyclic saturated hydrocarbon groups; the polycyclic saturated hydrocarbon group refers to a polycyclic group formed by two or more cyclic alkyl structures connected by spiro, bridge, fusion, etc. The carbon atoms in the cycloalkyl group can be further oxidized to form C(O). The cycloalkyl group includes "C 3-12 Cycloalkyl", "C 3-8 Cycloalkyl", "C 3-6 Cycloalkyl", "C 3-5 Preferably, the specific examples of the cycloalkyl group include but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,

[0288] Unless otherwise specified, the term "heterocycloalkyl" refers to a saturated cyclic group derived from a cycloalkyl group in which one or more ring carbon atoms are replaced by heteroatoms and / or heteroatomic groups. The heteroatoms and / or heteroatomic groups are generally selected from N, O, S, NO, SO, S(O)2, P(O), and NR, wherein the carbon atoms in the heterocyclic ring are optionally oxidized, i.e., forming -C(O); preferably, the heteroatoms are independently selected from 1-3 N and / or O. The heterocycloalkyl group includes "3-12 membered heterocycloalkyl", "3-8 membered heterocycloalkyl", "3-6 membered heterocycloalkyl", "3-5 membered heterocycloalkyl", "4-6 membered heterocycloalkyl", "5-6 membered heterocycloalkyl". The definition of the cycloalkyl group is the same as described above. "Heterocycloalkyl" includes but is not limited to

[0289] Unless otherwise specified, "cycloalkenyl" means that one or more ring bonds in the "cycloalkyl" are double bonds and the cycloalkenyl is not aromatic. The carbon atoms in the cycloalkenyl can be further oxidized, i.e., to form C(O). The cycloalkenyl can be fused to an aryl, heteroaryl, or heterocycloalkenyl, wherein the ring connected to the parent structure is a cycloalkenyl. The cycloalkenyl includes "3-12 membered cycloalkenyl", "3-8 membered cycloalkenyl", "3-6 membered cycloalkenyl", "3-5 membered cycloalkenyl", and "5-6 membered cycloalkenyl". The definition of "cycloalkyl" is the same as above. "Heterocycloalkenyl" includes but is not limited to

[0290] Unless otherwise specified, the term "heterocycloalkenyl" means that one or more ring bonds in the "heterocycloalkyl" are double bonds and are not aromatic. The "heterocycloalkyl" is the same as described above. The heterocycloalkenyl may be fused to an aryl or heteroaryl group, wherein the ring connected to the parent structure is a heterocycloalkenyl, etc. Preferably, the heteroatoms are independently selected from 1-3 N and / or O. The heterocycloalkenyl includes "3-12 membered heterocycloalkenyl", "3-8 membered heterocycloalkenyl", "3-6 membered heterocycloalkenyl", "3-5 membered heterocycloalkenyl", "5-6 membered heterocycloalkenyl". "Heterocycloalkenyl" includes but is not limited to

[0291] Unless otherwise specified, the term "aryl" refers to an unsaturated, usually aromatic, cyclic hydrocarbon group, which may be a single ring or multiple rings fused together. A fused ring aryl group refers to a group in which two or more cyclic structures share two adjacent atoms, and the ring directly connected to the parent structure is aromatic (the ring not directly connected to the parent structure is an aromatic ring or a non-aromatic ring). The aryl group may be fused to a heterocycloalkenyl or cycloalkenyl group, wherein the ring connected to the parent structure is an aryl group, etc. Preferably C 6-14 Aryl, preferably C 6-10 Aryl.

[0292] The "heteroaryl" described in the present invention refers to a monocyclic or polycyclic group with aromatic properties containing one or more heteroatoms in the ring, wherein the heteroatoms are generally selected from N, O, and S; preferably, the heteroatoms are independently selected from 1-3 N and / or O. In addition, the N and S atoms may be optionally oxidized and the N atoms may be optionally quaternized. The "heteroaryl" includes "monocyclic heteroaryl" and "fused-ring heteroaryl". The fused-ring heteroaryl refers to a group containing one or more heteroatoms formed by two or more cyclic structures sharing two adjacent atoms, and the ring directly connected to the parent structure has aromatic properties (the ring not directly connected to the parent structure is an aromatic ring or a non-aromatic ring). The heteroaryl group described in the present invention is preferably a "nitrogen-containing heteroaryl group", preferably a "5-6-membered nitrogen-containing aryl group". The heteroatom in the "nitrogen-containing heteroaryl group" contains at least one nitrogen atom, for example, only 1, 2 or 3 nitrogen atoms, or one nitrogen atom and one or two other heteroatoms (for example, S and / or O atoms), or two nitrogen atoms and one or two other heteroatoms. Specific examples of the heteroaryl group include, but are not limited to, furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, and pyrimidinyl.

[0293] In various parts of this disclosure, linking substituents are described. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood to be a linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl", it should be understood that the "alkyl" or "aryl" represents a linking alkylene group or arylene group, respectively.

[0294] Combinations of substituents and / or variables described herein are permissible only if these combinations result in stable compounds or useful synthetic intermediates. A stable compound or structure is one that is sufficiently robust to withstand chemical reactions, to be isolated to a useful degree of purity, and to be formulated into an efficacious therapeutic agent.

[0295] In the examples of this invention, the title compound names were derived from the compound structures using ChemDraw. If the compound name and structure are inconsistent, the structure can be determined by integrating relevant information and reaction routes. If other methods are unavailable for confirmation, the given compound structure will prevail.

[0296] The preparation methods of some compounds in the present invention refer to the preparation methods of the aforementioned similar compounds. Those skilled in the art should be aware that when using or referring to the preparation methods cited, the feed ratio of reactants, reaction solvent, reaction temperature, etc. can be appropriately adjusted according to the different reactants.

[0297] The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present invention. DETAILED DESCRIPTION

[0298] The structures of the compounds of the present invention were determined by nuclear magnetic resonance (NMR) mass spectroscopy. NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed using a Bruker Ascend 400 NMR instrument. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), deuterated chloroform (CDCl3), and heavy water (D2O), with tetramethylsilane (TMS) as the internal standard.

[0299] The thin layer chromatography silica gel plate used was HSGF254 silica gel plate from Yantai Jiangyou Silica Gel Development Co., Ltd. The specifications used for TLC were 0.20 mm ± 0.03 mm, and the preparative size was 20 × 20 cm. The column chromatography used 200-300 mesh silica gel from Qingdao Hailang Silica Gel Desiccant Co., Ltd. as the carrier.

[0300] The starting materials in the examples of the present invention are known and can be purchased commercially, or can be synthesized using or according to methods known in the art.

[0301] Unless otherwise specified, all reactions of the present invention are carried out under continuous magnetic stirring in a dry nitrogen or argon atmosphere, with dry solvents and reaction temperatures in degrees Celsius.

[0302] Unless otherwise specified, the percentage content (%) involved in the present invention refers to mass percentage for solid-liquid mixing and solid-solid mixing, and refers to volume percentage for liquid-liquid mixing.

[0303] General Preparation

[0304] The examples in Table 1 below were synthesized according to the general preparation principles.

[0305] Table 1

[0306] Intermediate 1

[0307] tert-Butyl (R)-3-((S)-3-((R)-3-amino-2,3-dihydrobenzofuran-5-yl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate

[0308] Reaction route:

[0309] Steps:

[0310] Step A: At 0°C under nitrogen, formic acid (75.99 g, 1650.92 mmol) was slowly added dropwise to a solution of triethylamine (142.92 g, 1415.07 mmol). Subsequently, a dichloromethane solution (786 mL) of 5-bromobenzofuran-3(2H)-one (100.00 g, 471.69 mmol) and a dichloromethane solution (153 mL) of [(R,R)-N-(2-amino-1,2-diphenylethyl)-p-toluenesulfonamido]chlorinated (mesitylene)ruthenium(II) (8.86 g, 13.95 mmol) were slowly added dropwise to the above solution. The reaction system was then stirred at room temperature for 16 hours.

[0311] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was quenched with ice water (1.5 L). The mixed solution was extracted with dichloromethane (700 mL × 2 times), and the organic phases were combined and washed sequentially with 0.5M hydrochloric acid solution (600 mL × 2 times), saturated sodium bicarbonate solution (400 mL × 2 times), and saturated sodium chloride solution (400 mL). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified on a silica gel column to obtain 100.00 g of crude (S)-5-bromo-2,3-dihydrobenzofuran-3-ol.

[0312] MS (ESI) M / Z: 197.1 [M-OH] + .

[0313] Step B: (S)-5-bromo-2,3-dihydrobenzofuran-3-ol (100.00 g, 467.02 mmol) was dissolved in toluene (280 mL) at 0°C under nitrogen. 1,8-diazabicyclo[5.4.0]undec-7-ene (85.00 g, 558.33 mmol) and diphenylphosphoryl azide (154.00 g, 559.59 mmol) were then added dropwise to the solution. The reaction was stirred at room temperature for 1 hour.

[0314] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched with ice water (1 L). The mixture was extracted with ethyl acetate (500 mL x 2), and the organic phases were combined and washed sequentially with saturated aqueous sodium carbonate (500 mL) and saturated aqueous sodium chloride (400 mL). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified on a silica gel column to yield 120.00 g of crude (R)-3-azido-5-bromo-2,3-dihydrobenzofuran.

[0315] Step C: (R)-3-azido-5-bromo-2,3-dihydrobenzofuran (120.00 g, 499.88 mmol) was dissolved in water / tetrahydrofuran (45 mL / 1 L) at 0°C under nitrogen. Triphenylphosphine (157.00 g, 598.57 mmol) was then added to the solution. The reaction was stirred at 50°C for 16 hours.

[0316] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was concentrated under reduced pressure. The residue was diluted with dichloromethane (300 mL) and stirred at 0°C. 4M hydrochloric acid-1,4-dioxane (125 mL) was added dropwise, and the mixture was filtered. The filter cake was rinsed with dichloromethane (100 mL x 2). The filter cake was collected and dried under vacuum to yield 70.00 g of (R)-5-bromo-2,3-dihydrobenzofuran-3-amine hydrochloride.

[0317] MS (ESI) M / Z: 197.1 [M-NH2] + .

[0318] Step D: Dissolve (R)-5-bromo-2,3-dihydrobenzofuran-3-amine hydrochloride (70.00 g, 279.42 mmol) in tetrahydrofuran (1.1 L) at 0°C. Add triethylamine (45.59 g, 450.53 mmol) and stir for 10 minutes. Then, add benzyloxycarbonyl succinimide (70.00 g, 280.88 mmol), warm to room temperature, and continue stirring for 1 hour.

[0319] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was slowly added to an ice-water solution (1 L) to quench the mixture. The mixture was extracted with ethyl acetate (800 mL × 2 times), and the organic phases were combined and washed sequentially with 0.5M hydrochloric acid (500 mL × 2 times), saturated aqueous sodium carbonate solution (500 mL), and saturated brine (300 mL). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified on a silica gel column to obtain 97.00 g of benzyl (R)-(5-bromo-2,3-dihydrobenzofuran-3-yl)carbamate.

[0320] MS (ESI) M / Z: 370.1 [M+23] + .

[0321] Step E: At 0°C under nitrogen, benzyl (R)-(5-bromo-2,3-dihydrobenzofuran-3-yl)carbamate (97.00 g, 278.58 mmol) and (tributyltin)methanol (103.19 g, 321.37 mmol) were dissolved in dry 1,4-dioxane (931 mL). Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (10.99 g, 13.99 mmol) was then added to the solution. The reaction was stirred at 90°C for 4 hours.

[0322] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was concentrated under reduced pressure. Water (1 L) was added to the residue to quench the mixture, and the mixture was extracted with ethyl acetate (800 mL x 2). The organic phases were combined and washed with saturated brine (300 mL). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified on a silica gel column to yield 52.00 g of benzyl (R)-(5-(hydroxymethyl)-2,3-dihydrobenzofuran-3-yl)carbamate.

[0323] MS (ESI) M / Z: 282.2 [M-OH] +.

[0324] Step F: At 0°C under nitrogen, dissolve benzyl (R)-(5-(hydroxymethyl)-2,3-dihydrobenzofuran-3-yl)carbamate (52.00 g, 173.73 mmol) in dry dichloromethane (870 mL). Phosphorus tribromide (71.00 g, 262.30 mmol) was slowly added dropwise to the solution. The reaction was stirred at room temperature for 4 hours.

[0325] After LCMS monitoring showed that the starting material disappeared, the reaction solution was slowly added to ice water (2.2 L) at 0 degrees Celsius with stirring to quench and separate the layers. The aqueous phase was extracted with dichloromethane (1.1 L), and the organic phases were combined. The organic phases were washed sequentially with saturated aqueous sodium bicarbonate solution (1.1 L) and saturated brine (550 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was slurried with petroleum ether, filtered, and the solid was collected to obtain 54.00 g of (R)-(5-(bromomethyl)-2,3-dihydrobenzofuran-3-yl)benzylcarbamate.

[0326] Step G: At -30°C under nitrogen, dissolve tert-butyl (R)-3-(2-((S)-4-benzyl-2-oxooxazolidin-3-yl)-2-oxoethyl)pyrrolidine-1-carboxylate (52.60 g, 135.41 mmol) in dry tetrahydrofuran (54 mL). Then, slowly add 1M lithium bistrimethylsilylamide (163 mL, 163.00 mmol) dropwise to the above system and stir for 30 minutes. Then, slowly add a solution of benzyl (R)-(5-(bromomethyl)-2,3-dihydrobenzofuran-3-yl)carbamate (54.00 g, 149.08 mmol) in tetrahydrofuran (297 mL) dropwise and stir for 30 minutes. Then, warm to 0°C and continue stirring for 1 hour.

[0327] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched by adding ice-cold saturated aqueous ammonium chloride (500 mL) at 0°C. The mixture was extracted with ethyl acetate (500 mL x 2), and the organic phases were combined and washed sequentially with 0.5 M hydrochloric acid (320 mL x 2), saturated aqueous sodium carbonate (320 mL x 2), and saturated brine (300 mL). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 89.00 g of crude product: (R)-tert-butyl 3-((S)-1-((S)-4-benzyl-2-oxooxazolidin-3-yl)-3-((R)-3-(((benzyloxy)carbonyl)amino)-2,3-dihydrobenzofuran-5-yl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate.

[0328] MS (ESI) M / Z: 570.2 [M-99] + .

[0329] Step H: At 0°C under nitrogen, tert-butyl (R)-3-((S)-1-((S)-4-benzyl-2-oxooxazolidin-3-yl)-3-((R)-3-(((benzyloxy)carbonyl)amino)-2,3-dihydrobenzofuran-5-yl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (89.00 g, 132.88 mmol) was dissolved in tetrahydrofuran (886 mL). A 30% aqueous solution of hydrogen peroxide (21.10 g, 186.18 mmol) in water (211 mL) and a solution of lithium hydroxide monohydrate (6.70 g, 159.67 mmol) in water (160 mL) were slowly added dropwise to the solution. The reaction system was then stirred at 0°C for 3 hours.

[0330] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was slowly quenched by the dropwise addition of an aqueous solution (268 mL) of sodium bisulfite (27.95 g, 268.60 mmol) at 0°C. The mixture was adjusted to pH 2 with hydrochloric acid and then extracted with ethyl acetate (300 mL x 2). The organic phases were combined and washed with saturated brine (300 mL). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. This afforded 89.00 g of crude (S)-3-((R)-3-(((benzyloxy)carbonyl)amino)-2,3-dihydrobenzofuran-5-yl)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)propanoic acid.

[0331] Step I: (S)-3-((R)-3-(((benzyloxy)carbonyl)amino)-2,3-dihydrobenzofuran-5-yl)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)propanoic acid (89.00 g, 174.31 mmol) was dissolved in tetrahydrofuran (870 mL) at room temperature under nitrogen. Tert-butyl N,N'-diisopropylcarbamate (121.91 g, 608.55 mmol) was then added to the solution. The reaction was stirred at 65°C for 16 hours.

[0332] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched by adding water (1000 mL). The mixture was extracted with ethyl acetate (1000 mL x 2). The organic phases were combined and washed sequentially with saturated aqueous sodium bicarbonate (500 mL x 2) and saturated aqueous sodium chloride (300 mL). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 20.00 g of tert-butyl (R)-3-((S)-3-((R)-3-(((benzyloxy)carbonyl)amino)-2,3-dihydrobenzofuran-5-yl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate.

[0333] MS (ESI) M / Z: 467.3 [M-99] + .

[0334] Step J: Dissolve tert-butyl (R)-3-((S)-3-((R)-3-(((benzyloxy)carbonyl)amino)-2,3-dihydrobenzofuran-5-yl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (12.70 g, 22.41 mmol) and 10% palladium on carbon (3.81 g) in isopropanol (140 mL) at room temperature under a hydrogen atmosphere. Replace the hydrogen atmosphere with air under vacuum three times and stir at room temperature for 16 hours.

[0335] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 9.60 g of tert-butyl (R)-3-((S)-3-((R)-3-amino-2,3-dihydrobenzofuran-5-yl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate.

[0336] MS (ESI) M / Z: 455.2 [M+23] + .

[0337] Example 246

[0338] (2S,2'S,2'S)-3,3',3'-((nitrilotris(methylene))tris(benzene-4,1-diyl)tris(2-(((R)-pyrrolidin-3-yl)propanoic acid)

[0339] It can also be prepared according to the following steps:

[0340] Reaction route:

[0341] Steps:

[0342] Step A: Dissolve tert-butyl (R)-3-((S)-3-(4-bromophenyl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (1 g, 2.21 mmol) and 3-oxobenzo[d]isothiazole-2(3H)-carbaldehyde 1,1-dioxide (1.1 g, 5.53 mmol) in dry N,N-dimethylformamide (11 mL) at 0°C. Then, sodium carbonate (702 mg, 6.63 mmol), 1,4-bis(diphenylphosphino)butane (188 mg, 0.44 mmol), triethylsilane (512 mg, 4.42 mmol), and palladium acetate (100 mg, 0.44 mmol) were added to the solution. The air was evacuated and replaced with nitrogen three times under vacuum. The reaction was stirred at 75°C for 16 hours.

[0343] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was added to ice water (50 mL) to quench the mixture. The mixed solution was extracted with ethyl acetate (25 mL × 3 times), and the organic phases were combined and washed with saturated brine (30 mL × 2 times). It was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column to obtain 230 mg of (R)-3-((S)-1-(tert-butoxy)-3-(4-formylphenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester.

[0344] MS (ESI) M / Z: 426.2 [M+23] + .

[0345] Step B: Dissolve tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(4-formylphenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (230 mg, 0.57 mmol) in isopropanol (2.2 mL) at 0°C under nitrogen. Add a 3.5 M amine solution in isopropanol (0.3 mL) and acetic acid (51 mg, 0.86 mmol) sequentially to the solution, warm to room temperature, and stir for 1 hour. Then, slowly add sodium acetate borohydride (604 mg, 2.85 mmol), warm to 70°C, and continue stirring for 3 hours.

[0346] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was added to ice water (30 mL) to quench the reaction. The mixture was extracted with ethyl acetate (20 mL x 3), and the organic phases were combined and washed with saturated brine (20 mL x 2). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 180 mg of 3,3'-((2S,2'S)-((azadiylbis(methylene))bis(4,1-phenylene))-bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate).

[0347] MS (ESI) M / Z: 792.4 [M+H] + .

[0348] Step C: 3,3'-((2S,2'S)-((azadiylbis(methylene))bis(4,1-phenylene))-bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate) (25 mg, 0.03 mmol) and (R)-tert-butyl 3-((S)-3-(4-(bromomethyl)phenyl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (18 mg, 0.04 mmol) were dissolved in acetonitrile (1 mL) at room temperature. Potassium carbonate (9 mg, 0.06 mmol) and potassium iodide (11 mg, 0.06 mmol) were then added to the solution. The reaction was stirred at 40°C for 16 hours.

[0349] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched by adding ice water (30 mL). The mixture was extracted with ethyl acetate (20 mL × 3 times), and the organic phases were combined and washed with saturated brine (20 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 10 mg of 3,3',3'-((2S,2'S,2'S)((nitrilotris(methylene))tris(benzene-4,1-diyl)tris(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R,3'R)-tris(pyrrolidine-1-carboxylate).

[0350] Step D: 3,3',3'-((2S,2'S,2'S)((nitrilotris(methylene))tris(benzene-4,1-diyl)tris(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R,3'R)-tris(pyrrolidine-1-carboxylate) (10 mg, 0.08 mmol) was dissolved in dry dichloromethane (0.5 mL) at room temperature. Subsequently, 4 M hydrochloric acid-1,4-dioxane solution (2 mL) was added to the above solution. The reaction system was then stirred at room temperature for 16 hours.

[0351] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was filtered, the filter cake was rinsed with dichloromethane (10 mL×3 times), and the filter cake was concentrated under reduced pressure to obtain 4.95 mg of (2S,2'S,2'S)-3,3',3'-((nitrilotris(methylene))tris(benzene-4,1-diyl)tris(2-(((R)-pyrrolidin-3-yl)propionic acid) hydrochloride.

[0352] MS (ESI) M / Z: 711.4 [M+H] + .

[0353] 1 H NMR (400MHz, D2O): δ7.24(d,J=8.0Hz,6H),7.20(d,J=8.0Hz,6H),4.23(s,6H),3.61-3.51(m,3H),3.42-3.32(m,3H),3.26-3. 15(m,3H),3.06-3.00(m,3H),2.95-2.76(m,6H),2.74-2.64(m,3H),2.59-2.45(m,3H),2.20-2.05(m,3H),1.78-1.62(m,3H).

[0354] Example 135

[0355] (2S,2'S)-3,3'-(((1-(4-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)phenyl)piperidin-4-yl)azepinediyl)bis(methylene)bis(3,1-phenylene))bis(2-(R)pyrrolidin-3-yl)propanoic acid)

[0356] It can also be prepared according to the following steps:

[0357] Reaction route:

[0358] Steps:

[0359] Step A: At -30°C under nitrogen, slowly add 1M lithium bistrimethylsilylamide (31 mL, 30.92 mmol) dropwise to a solution of (R)-tert-butyl 3-(2-((S)-4-benzyl-2-oxooxazolidin-3-yl)-2-oxoethyl)pyrrolidine-1-carboxylate (10 g, 25.77 mmol) in tetrahydrofuran (10 mL) and stir for 0.5 hour. Subsequently, slowly add a solution of 1-bromo-4-(bromomethyl)benzene (7.67 g, 30.92 mol) in tetrahydrofuran (15 mL) and stir for 1 hour. Then, warm the reaction system to 0°C and continue stirring for 2 hours.

[0360] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was slowly added to an ice-cold saturated ammonium chloride solution (200 mL) to quench. The mixed solution was extracted with ethyl acetate (100 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (200 mL × 2 times). Then, it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column to obtain 10 g of tert-butyl 3-(S)-1-(S)-4-benzyl-2-oxooxazolidin-3-yl)-3-(4-bromophenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate.

[0361] MS (ESI) M / Z: 457.0 [M-99] + .

[0362] Step B: Dissolve tert-butyl 3-(S)-1-(S)-4-benzyl-2-oxooxazolidin-3-yl)-3-(4-bromophenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (10 g, 18 mmol) in tetrahydrofuran (128 mL) at 0°C. Then, slowly add a 33% aqueous solution of hydrogen peroxide (31 mL, 27 mmol) and a 30 mL aqueous solution of lithium hydroxide monohydrate (1.2 g, 27 mmol). The reaction system is then stirred for 3 hours.

[0363] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was slowly quenched by the dropwise addition of an aqueous solution of sodium bisulfite (4 g, 36.36 mmol) (65 mL) at 0°C. The pH was adjusted to >12 with saturated aqueous sodium hydroxide. The mixture was extracted with methyl tert-butyl ether (100 mL x 4), and the resulting aqueous phase was adjusted to pH 3 with 8 M hydrochloric acid. The aqueous phase was then extracted with ethyl acetate (100 mL x 3), and the combined organic phases were washed with saturated brine (50 mL x 2). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield 5.5 g of (S)-3-(4-bromophenyl)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)propanoic acid.

[0364] MS (ESI) M / Z: 420.0 [M+23] + .

[0365] Step C: Dissolve (S)-3-(4-bromophenyl)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)propanoic acid (5.5 g, 13.85 mmol) and 2-tert-butyl-1,3-diisopropylisourea (9.70 g, 48.49 mmol) in tetrahydrofuran (20 mL) at room temperature. Evacuate the mixture three times to displace nitrogen. Stir the reaction at 65°C for 16 hours.

[0366] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was filtered and the filter cake was rinsed with tetrahydrofuran (50 mL x 4). Water (100 mL) was added to the filtrate to quench the mixture, and the mixture was extracted with ethyl acetate (50 mL x 3 times). The organic phases were combined and washed with saturated aqueous sodium chloride solution (50 mL x 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 5 g of tert-butyl (R)-3-((S)-3-(4-bromophenyl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate.

[0367] MS (ESI) M / Z: 476.2 [M+23] + .

[0368] Step D: tert-Butyl (R)-3-((S)-3-(4-bromophenyl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (500 mg, 1.1 mmol), benzylpiperidin-4-ylcarbamate (260 mg, 1.1 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (130 mg, 0.22 mmol), cesium carbonate (720 mg, 2.2 mmol), and tris(dibenzylideneacetone)dipalladium (100 mg, 0.11 mmol) were dissolved in dry 1,4-dioxane (6 mL) at room temperature. The atmosphere was replaced with nitrogen under vacuum three times, and the reaction system was stirred at 100°C for 16 hours.

[0369] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was filtered and the filter cake was rinsed with tetrahydrofuran (50 mL x 4). The filtrate was quenched with water (100 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined and washed with saturated aqueous sodium chloride solution (100 mL x 2). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 170 mg of (R)-tert-butyl 3-((S)-3-(4-(4-(((benzyloxy)carbonyl)amino)piperidin-1-yl)phenyl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate.

[0370] MS (ESI) M / Z: 608.4 [M+H] + .

[0371] Step E: (R)-tert-Butyl 3-((S)-3-(4-(4-(((benzyloxy)carbonyl)amino)piperidin-1-yl)phenyl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (170 mg, 0.28 mmol) and 10% palladium on carbon (35 mg) were dissolved in isopropanol (5 mL) at room temperature. The hydrogen atmosphere was replaced by air under vacuum three times, and the reaction was stirred at room temperature for 16 hours.

[0372] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was filtered, the filter cake was rinsed with tetrahydrofuran (50 mL×4 times), all the filtrates were combined and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give 100 mg of (R)-3-((S)-3-(4-(4-aminopiperidin-1-yl)phenyl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester.

[0373] MS (ESI) M / Z: 474.3 [M+H] + .

[0374] Step F: Dissolve tert-butyl (R)-3-((S)-3-(4-(4-aminopiperidin-1-yl)phenyl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (60 mg, 0.13 mmol), tert-butyl (R)-3-((S)-3-(3-(bromomethyl)phenyl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (135 mg, 0.30 mmol), potassium carbonate (45 mg, 0.32 mmol), and potassium iodide (46 mg, 0.30 mmol) in acetonitrile (4 mL) at room temperature. The air was evacuated and replaced with nitrogen three times under vacuum. The reaction system was stirred at 40°C for 3 hours.

[0375] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was slowly added to an ice-water solution (40 mL) to quench the reaction. The mixture was extracted with ethyl acetate (20 mL × 3 times), and the organic phases were combined and washed with saturated brine (20 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column to obtain 27 mg of 3,3'-di-tert-butyl((2S,2'S)-(((1-(4-((S)-3-(tert-butyloxy)-2-((R)-1-(tert-butyloxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)piperidin-4-yl)azinediyl)bis(methylene)bis(3,1-phenylene))bis(3-(tert-butyloxy)-3-oxypropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate).

[0376] MS (ESI) M / Z: 575.0 [(M-100) / 2+H]+ .

[0377] Step G: 3,3'-di-tert-butyl((2S,2'S)-(((1-(4-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)piperidin-4-yl)azinediyl)bis(methylene)bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxypropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate) (27 mg, 0.022 mmol) was dissolved in dry dichloromethane (1 mL) at room temperature. 4M hydrochloric acid-1,4-dioxane (2 mL) was then slowly added dropwise to the solution. The reaction was stirred at room temperature for 16 hours.

[0378] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was filtered and the filter cake was rinsed with dichloromethane (10 mL x 2). The resulting filter cake was purified by a neutral reverse-phase column and lyophilized to obtain 2.32 mg of (2S,2'S)-3,3'-(((1-(4-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)phenyl)piperidin-4-yl)azepinediyl)bis(methylene)bis(3,1-phenylene))bis(2-(R)pyrrolidin-3-yl)propanoic acid) hydrochloride.

[0379] MS (ESI) M / Z: 780.2 [M+H] + .

[0380] 1 H NMR(400MHz,D2O)δ7.45-6.97(m,12H),4.36(s,4H),3.70(d,J=12.4Hz,1H),3.60(d,J=11.6Hz,1H),3.57-3.41(m,4H),3.40-3.29(m,3H ),3.26-3.13(m,3H),3.04-2.87(m,5H),2.85-2.63(m,6H),2.50-2.33(m,6H),2.28-2.00(m,6H),1.91-1.75(m,1H),1.74-1.59(m,3H).

[0381] Example 216

[0382] (2S,2'S)-3,3'-(((1-(3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)phenyl)piperidin-4-yl)azepinediyl)bis(methylene)bis(3,1-phenylene))bis(2-((R)-pyrrolidin-3-yl)propanoic acid)

[0383] It can also be prepared according to the following steps:

[0384] Reaction route:

[0385] Steps:

[0386] Step A: In an ice-water bath, tert-butyl (R)-3-((S)-3-(3-bromophenyl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (500 mg, 1.10 mmol), benzyl piperidin-4-ylcarbamate (260 mg, 1.11 mmol), cesium carbonate (720 mg, 2.21 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (130 mg, 0.22 mmol), and tris(dibenzylideneacetone)dipalladium (441 mg, 0.48 mmol) were dissolved in 1,4-dioxane (5.5 mL). The atmosphere was replaced with nitrogen under vacuum three times, and the reaction system was stirred at 100°C for 16 hours.

[0387] After LCMS monitoring showed the disappearance of the starting material, ice water (50 mL) was added to the reaction solution to quench the reaction. The mixed solution was extracted with ethyl acetate (40 mL × 3 times), and the organic phases were combined and washed with saturated brine (80 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 280 mg of (R)-3-((S)-3-(3-(4-(((benzyloxy)carbonyl)amino)piperidin-1-yl)phenyl)-1-(tert-butyloxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester.

[0388] MS (ESI) M / Z: 608.4 [M+H] + .

[0389] Step B: Dissolve tert-butyl (R)-3-((S)-3-(3-(4-(((benzyloxy)carbonyl)amino)piperidin-1-yl)phenyl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (280 g, 0.46 mmol) and 10% palladium on carbon (600 mg, 0.56 mmol) in methanol (14 mL) at room temperature. The hydrogen atmosphere was replaced by air under vacuum three times, and the reaction system was stirred at room temperature for 16 hours.

[0390] After LCMS monitoring showed the disappearance of the starting material, the mixed solution was filtered and the filtrate was concentrated under reduced pressure to obtain 197 mg of tert-butyl (R)-3-((S)-3-(3-(4-aminopiperidin-1-yl)phenyl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate.

[0391] MS (ESI) M / Z: 474.3 [M+H] + .

[0392] Step C: Dissolve (R)-tert-butyl 3-((S)-3-(3-(4-aminopiperidin-1-yl)phenyl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (190 mg, 0.40 mmol), (R)-tert-butyl 3-((S)-1-(tert-butoxy)-3-(3-formylphenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (486 mg, 1.21 mmol), and acetic acid (24 mg, 0.40 mmol) in isopropanol (13.0 mL) at room temperature under nitrogen and stir for 15 minutes. Then, add sodium cyanoborohydride (126 mg, 2.00 mmol) to the reaction mixture, heat to 75°C, and continue stirring for 4 hours.

[0393] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched by adding water (80 mL). The mixture was extracted with ethyl acetate (40 mL × 3 times), and the organic phases were combined and washed with saturated brine (30 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 250 mg of tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(3-(((1-(3-(S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)piperidin-4-yl)amino)methyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate.

[0394] MS (ESI) M / Z: 861.4 [M+H] + .

[0395] Step D: Tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(3-(((1-(3-(S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)piperidin-4-yl)amino)methyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (150 mg, 0.17 mmol), tert-butyl (R)-3-((S)-3-(3-(bromomethyl)phenyl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (98 mg, 0.21 mmol), potassium carbonate (48 mg, 0.34 mmol) and potassium iodide (56 mg, 0.34 mmol) were dissolved in acetonitrile (1.7 mL) at room temperature under nitrogen. The reaction system was then stirred at 40°C for 4 hours.

[0396] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched by adding water (30 mL). The mixture was extracted with ethyl acetate (20 mL x 3), and the organic phases were combined and washed with saturated brine (30 mL x 2). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 35 mg of 3,3'-di-tert-butyl((2S,2'S)-(((1-(3-((S)-3-(tert-butyloxy)-2-((R)-1-(tert-butyloxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)piperidin-4-yl)azinediyl)bis(methylene)bis(3,1-phenylene))bis(3-(tert-butyloxy)-3-oxypropane-1,2-diyl))3R,3'R)-bis(pyrrolidine-1-carboxylate).

[0397] MS (ESI) M / Z: 575.0 [(M-100) / 2+H] +

[0398] Step E: In an ice-water bath under nitrogen protection, 3,3'-di-tert-butyl((2S,2'S)-(((1-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)piperidin-4-yl)azinediyl)bis(methylene)bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxypropane-1,2-diyl))3R,3'R)-bis(pyrrolidine-1-carboxylate) (30 mg, 0.03 mmol) was dissolved in dichloromethane (1.7 mL). Subsequently, 4M hydrochloric acid-dioxane (98 mg, 0.21 mmol) was added dropwise to the above solution. The reaction system was then stirred at room temperature for 16 hours.

[0399] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was filtered, the residual solid was rinsed with dichloromethane (10 mL×2 times), and the filter cake was concentrated under reduced pressure to obtain 13.19 mg of (2S,2'S)-3,3'-(((1-(3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)phenyl)piperidin-4-yl)azepinediyl)bis(methylene)bis(3,1-phenylene))bis(2-((R)-pyrrolidin-3-yl)propanoic acid) hydrochloride.

[0400] MS (ESI) M / Z: 780.6 [M+H] + .

[0401] 1H NMR(400MHz,D2O)δ7.53-7.06(m,12H),4.41(s,4H),3.85-3.64(m,3H),3.63-3.43(m,5H),3.42-3.32(m,3H),3.29-3.16(m,3H),3.12 -3.00(m,3H),2.99-2.75(m,6H),2.73-2.61(m,3H),2.60-2.28(m,6H),2.21-1.99(m,4H),1.80-1.61(m,3H).

[0402] Example 11

[0403] (2S,2'S)-3,3'-(((3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)benzyl)azepinediyl)bis(methylene))bis(2,3-dihydrobenzo[b][1,4]dioxin-7,5-diyl))bis(2-(((R)-pyrrolidin-3-yl)propanoic acid)

[0404] It can also be prepared according to the following steps:

[0405] Reaction route:

[0406] Steps:

[0407] Step A: Dissolve methyl 5-bromo-2,3-dihydroxybenzoate (7 g, 28.46 mmol) and potassium carbonate (15.7 g, 113.84 mmol) in N,N-dimethylformamide (142 mL) at 0°C. Slowly add 1,2-dibromoethane (10.7 g, 56.91 mmol) dropwise to the solution. The reaction mixture is stirred at 100°C for 3 hours.

[0408] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was quenched by adding ice water (100 mL). The mixture was extracted with ethyl acetate (200 mL × 3 times), and the organic phases were combined and washed with saturated brine (200 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 7 g of methyl 7-bromo-2,3-dihydrobenzo[b][1,4]dioxin-5-carboxylate.

[0409] MS (ESI) M / Z: 273.0 [M+H] + .

[0410] Step B: In an ice-water bath under nitrogen, dissolve methyl 7-bromo-2,3-dihydrobenzo[b][1,4]dioxin-5-carboxylate (7 g, 25.73 mmol) in dry tetrahydrofuran (128 mL). Then, slowly add 2.5 M lithium aluminum tetrahydride (20.6 mL, 51.47 mmol) dropwise to the solution. The reaction mixture is stirred at room temperature for 1 hour.

[0411] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was quenched by adding ice water (20 mL). The mixture was filtered, and the filter cake was rinsed with tetrahydrofuran (50 mL x 2). All filtrates were collected and extracted with ethyl acetate (200 mL x 3). The organic phases were combined and washed with saturated brine (200 mL x 2). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. 6.2 g of (7-bromo-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)methanol was obtained.

[0412] MS (ESI) M / Z: 227.9 [M-17] + .

[0413] Step C: In an ice-water bath under nitrogen, dissolve (7-bromo-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)methanol (6.2 g, 25.41 mmol) in dichloromethane (127 mL). Phosphorus tribromide (10 g, 38.11 mmol) was then added dropwise to the solution. The reaction was stirred at room temperature for 4 hours.

[0414] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was added to ice water (100 mL) for quenching. The mixture was extracted with ethyl acetate (200 mL x 3), and the organic phases were combined and washed with saturated brine (200 mL x 2). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 6.8 g of 7-bromo-5-(bromomethyl)-2,3-dihydrobenzo[b][1,4]dioxane.

[0415] Step D: Dissolve tert-butyl (R)-3-(2-((S)-4-benzyl-2-oxooxazolidin-3-yl)-2-oxoethyl)pyrrolidine-1-carboxylate (5 g, 13.07 mmol) in dry tetrahydrofuran (5.2 mL) at -30°C under nitrogen. Slowly add 1 M lithium bistrimethylsilylamide (15.69 mL, 15.69 mmol) dropwise to the solution and stir for 30 minutes. Then, slowly add 7-bromo-5-(bromomethyl)-2,3-dihydrobenzo[b][1,4]dioxane (4.8 g, 15.69 mmol) in tetrahydrofuran (7.8 mL) dropwise and continue stirring for 1 hour. Then, warm the reaction mixture to room temperature and continue stirring for 2 hours.

[0416] After LCMS monitoring showed the disappearance of the starting material, the mixture was added to an ice-cold saturated ammonium chloride solution (50 mL) to quench the mixture. The mixture was extracted with ethyl acetate (20 mL × 3 times), and the organic phases were combined and washed with saturated brine (20 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. This yielded 3 g of tert-butyl 3-((S)-1-(S)-4-benzyl-2-oxooxazolidin-3-yl)-3-(7-bromo-2,3-dihydrobenzo[b][1,4]dioxol-5-yl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate.

[0417] MS (ESI) M / Z: 637.0 [M+23] + .

[0418] Step E: Dissolve tert-butyl 3-((S)-1-(S)-4-benzyl-2-oxooxazolidin-3-yl)-3-(7-bromo-2,3-dihydrobenzo[b][1,4]dioxol-5-yl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (3 g, 4.88 mmol) in tetrahydrofuran (32 mL) in an ice-water bath. Then, slowly add a 33% aqueous solution of hydrogen peroxide (7 mL, 7.33 mmol) and a solution of lithium hydroxide (31.9 mg, 7.33 mmol) in water (7 mL) to the solution. Stir the reaction for 4 hours.

[0419] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched with sodium bisulfite solution (8 mL), adjusted to pH > 12 with saturated sodium hydroxide solution, and extracted with methyl tert-butyl ether (100 mL x 4). The aqueous phase was then adjusted to pH 3 with 8M hydrochloric acid solution and extracted with ethyl acetate (100 mL x 3). The organic phases were combined and washed with saturated brine (50 mL x 2). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield 2 g of (S)-3-(7-bromo-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)propanoic acid.

[0420] MS (ESI) M / Z: 400.0 [M-55] + .

[0421] Step F: (S)-3-(7-Bromo-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)propanoic acid (2 g, 4.4 mmol) and 2-tert-butyl-1,3-diisopropylisourea (3 g, 15.4 mmol) were dissolved in dry tetrahydrofuran (5.5 mL) under nitrogen at room temperature. The reaction was stirred at 65°C for 4 hours.

[0422] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was filtered and the filter cake was rinsed with tetrahydrofuran (50 mL x 4). The filtrate was quenched with water (100 mL) and extracted with ethyl acetate (60 mL x 3). The organic phases were combined and washed with saturated brine (60 mL x 2). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 2 g of tert-butyl (R)-3-((S)-3-(7-bromo-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate.

[0423] MS (ESI) M / Z: 412.0 [M-99] + .

[0424] Step G: Dissolve tert-butyl (R)-3-((S)-3-(7-bromo-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (2 g, 3.91 mmol), 3-oxobenzo[d]isothiazole-2(3H)-carbaldehyde 1,1-dioxide (2.06 g, 9.78 mmol), palladium acetate (177 mg, 0.78 mmol), 1,4-bis(diphenylphosphino)butane (333 mg, 0.78 mmol), sodium carbonate (1.24 g, 11.73 mmol), and triethylsilane (907 mg, 7.82 mmol) in dry N,N-dimethylformamide (20 mL) at room temperature. Evacuate the air and replace with nitrogen three times. Stir the reaction at 75°C for 16 hours.

[0425] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was added to ice water (100 mL) to quench the mixture. The mixture was extracted with ethyl acetate (30 mL × 3 times), and the organic phases were combined and washed with saturated brine (40 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 1 g of tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(7-formyl-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate.

[0426] MS (ESI) M / Z: 484.2 [M+23] + .

[0427] Step H: Dissolve tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(7-formyl-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (300 mg, 0.65 mmol) in isopropanol (3.5 mL) at room temperature under nitrogen. Add 3.5 M ammonia in isopropanol (0.33 mL, 1.17 mmol) and acetic acid (59 mg, 0.98 mmol) dropwise to the solution and stir for 1 hour. Then, add sodium cyanoborohydride (410 mg, 6.5 mmol), raise the temperature to 70°C, and continue stirring for 4 hours.

[0428] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was added to ice water (100 mL) for quenching. The mixture was extracted with ethyl acetate (60 mL × 3 times), and the organic phases were combined and washed with saturated brine (60 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 200 mg of 3,3'-di-tert-butyl((2S,2'S)-((azadiylbis(methylene))bis(2,3-dihydrobenzo[b][1,4]dioxol-7,5-diyl)bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate) and 90 mg of 3,3',3'-((2S,2'S,2'S)-((nitrilotris(methylene))tris(2,3-dihydrobenzo[b][1,4]dioxol-7,5-diyl))-tris(3-(tert-butoxy)-3-oxopropane-1,2-diyl)(3R,3'R,3'R)-tris(pyrrolidine-1-carboxylate).

[0429] MS (ESI) M / Z: 908.3 [M+H] + .

[0430] MS (ESI) M / Z: 627.4 [(M-100) / 2+H] + .

[0431] Step I: 3,3'-di-tert-butyl((2S,2'S)-((azadiylbis(methylene))bis(2,3-dihydrobenzo[b][1,4]dioxo-7,5-diyl)bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate) (200 mg, 0.22 mmol), (R)-tert-butyl 3-((S)-3-(3-(bromomethyl)phenyl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (124 mg, 0.26 mmol), potassium carbonate (61 mg, 0.44 mmol) and potassium iodide (73 mg, 0.44 mmol) were dissolved in acetonitrile (7.5 mL) at room temperature. The reaction was then stirred at 40°C for 5 hours.

[0432] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched by adding ice water (100 mL). The mixture was extracted with ethyl acetate (30 mL x 3), and the organic phases were combined and washed with saturated brine (30 mL x 2). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 180 mg of 3,3'-di-tert-butyl((2S,2'S)-(((3-((S)-3-(tert-butyloxy)-2-((R)-1-(tert-butyloxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)benzyl)azinediyl)bis(methylene))bis(2,3-dihydrobenzo[b][1,4]dioxo-7,5-diyl))bis-(3-(tert-butyloxy)-3-oxypropane-1,2-diyl)(3R,3'R)-bis(pyrrolidine-1-carboxylate).

[0433] MS (ESI) M / Z: 598.5 [(M-100) / 2+H] + .

[0434] Step J: 3,3'-di-tert-butyl((2S,2'S)-(((3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)benzyl)azinediyl)bis(methylene))bis(2,3-dihydrobenzo[b][1,4]dioxo-7,5-diyl))bis-(3-(tert-butoxy)-3-oxypropane-1,2-diyl)(3R,3'R)-bis(pyrrolidine-1-carboxylate) (180 mg, 0.14 mmol) was dissolved in 4M hydrochloric acid-1,4-dioxane (8 mL) at room temperature. The reaction was stirred for 4 hours.

[0435] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was filtered, the filter cake was rinsed with dichloromethane (10 mL×2 times), the filter cake was collected, and concentrated under reduced pressure to obtain 61.58 mg of (2S,2'S)-3,3'-(((3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)benzyl)azepinediyl)bis(methylene))bis(2,3-dihydrobenzo[b][1,4]dioxin-7,5-diyl))bis(2-(((R)-pyrrolidin-3-yl)propanoic acid) hydrochloride.

[0436] MS (ESI) M / Z: 827.4 [M+H] + .

[0437] 1H NMR(400MHz,D2O)δ7.42-7.35(m,2H),7.23-7.20(m,2H),6.74(s,2H),6.71 (s,2H),4.41-4.28(m,8H),4.25(s,2H),4.16(s,4H),3.66-3.56(m,3H),3. 49-3.39(m,3H),3.34-3.22(m,3H),3.11-3.00(m,3H),2.94-2.80(m,4H),2 .79-2.70(m,2H),2.66-2.45(m,6H),2.22-2.09(m,3H),1.83-1.67(m,3H).

[0438] Example 247

[0439] (2S,2'S,2"S)-3,3',3"-((nitrilotris(methylene))tris(2,3-dihydrobenzo[b][1,4]dioxetine-7,5-diyl))tris(2-(((R)-pyrrolidin-3-yl)propanoic acid

[0440] It can also be prepared according to the following steps:

[0441] Reaction route:

[0442] Steps:

[0443] Step A: tert-Butyl 3,3',3"-((2S,2'S,2"S)-((nitrilotris(methylene))tris(2,3-dihydrobenzo[b][1,4]dioxetine-7,5-diyl))-tris(3-(tert-butoxy)-3-oxopropane-1,2-diyl)(3R,3'R,3"R)-tris(pyrrolidine-1-carboxylate) (90 mg, 0.07 mmol) mL) was dissolved in dichloromethane (0.5 mL) at room temperature. 4 M hydrochloric acid-1,4-dioxane solution (1.5 mL) was then added dropwise to the solution. The reaction was stirred for 4 hours.

[0444] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was filtered, the filter cake was rinsed with dichloromethane (10 mL×2 times), the filter cake was collected, and concentrated under reduced pressure to obtain 13.12 mg of (2S,2'S,2"S)-3,3',3"-((nitrilotris(methylene))tris(2,3-dihydrobenzo[b][1,4]dioxetine-7,5-diyl))tris(2-(((R)-pyrrolidin-3-yl)propanoic acid) hydrochloride.

[0445] MS (ESI) M / Z: 885.4 [M+H] + .

[0446] 1 H NMR(400MHz,D2O)δ6.63(s,3H),6.61(s,3H),4.32-4.16(m,12H),4.05(s,6H),3.50(m,3H),3.39-3.29(m,3H),3.23 -3.13(m,3H),2.94(m,3H),2.75(m,3H),2.67-2.56(m,3H),2.52-2.33(m,6H),2.12-1.99(m,3H),1.72-1.57(m,3H).

[0447] Example 13

[0448] (2S,2'S)-3,3'-(((3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)benzyl)azepinediyl)bis(methylene))bis(2,3-dihydrobenzo[b][1,4]dioxetane-8,6-diyl))bis-(2-(((R)-pyrrolidin-3-yl)propanoic acid)

[0449] It can also be prepared according to the following steps:

[0450] Reaction route:

[0451] Steps:

[0452] Step A: In an ice-water bath under nitrogen, dissolve 3-bromo-4-hydroxy-5-methoxybenzaldehyde (10 g, 43.48 mmol) in dichloromethane (167 mL). Then, slowly add boron tribromide (96 mL, 95.65 mmol) dropwise to the solution and stir for 20 minutes. The reaction mixture is then stirred at room temperature for 2 hours.

[0453] After LCMS monitoring showed the disappearance of the starting material, methanol (10 mL) was added to the reaction solution to quench the mixture. The mixture was added to ice water (50 mL), and a solid precipitated. The solid was filtered and the filter cake was rinsed with ice water (50 mL × 3 times). The solid was collected and dried in vacuo to obtain 8.4 g of 3-bromo-4,5-dihydroxybenzaldehyde.

[0454] MS (ESI) M / Z: 216.9 [M+H] + .

[0455] Step B: In an ice-water bath under nitrogen, dissolve 3-bromo-4,5-dihydroxybenzaldehyde (8.4 g, 38.9 mmol) and potassium carbonate (21.5 g, 155.6 mmol) in N,N-dimethylformamide (195 mL). Then, slowly add 1,2-dibromoethane (18.3 g, 97.2 mmol) dropwise to the solution. The reaction mixture is stirred at 100°C for 3 hours.

[0456] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was quenched by adding ice water (700 mL). The mixture was extracted with ethyl acetate (200 mL x 3), and the organic phases were combined and washed with saturated brine (200 mL x 2). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 5.7 g of 8-bromo-2,3-dihydrobenzo[b][1,4]dioxane-6-carboxylic acid.

[0457] MS (ESI) M / Z: 243.0 [M+H] + .

[0458] Step C: In an ice-water bath under nitrogen, dissolve 8-bromo-2,3-dihydrobenzo[b][1,4]dioxane-6-carboxylic acid (5.7 g, 23.55 mmol) in methanol (118 mL). Then, slowly add sodium borohydride (1.34 g, 35.33 mmol). The reaction mixture is stirred at room temperature for 1 hour.

[0459] After LCMS monitoring showed that the starting material disappeared, the mixed solution was filtered, and the filtrate was collected and concentrated under reduced pressure to obtain 6 g of (8-bromo-2,3-dihydrobenzo[b][1,4]dioxan-6-yl)methanol.

[0460] MS (ESI) M / Z: 227.0 [M-17] + .

[0461] Step D: In an ice-water bath under nitrogen, dissolve (8-bromo-2,3-dihydrobenzo[b][1,4]dioxan-6-yl)methanol (6 g, 24.59 mmol) in dichloromethane (123 mL). Then, slowly add phosphorus tribromide (10 g, 36.88 mmol) to the solution. Stir the reaction at room temperature for 4 hours.

[0462] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was quenched by adding ice water (100 mL). The mixture was extracted with ethyl acetate (200 mL x 3), and the organic phases were combined and washed with saturated brine (200 mL x 2). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 5.4 g of 5-bromo-7-(bromomethyl)-2,3-dihydrobenzo[b][1,4]dioxane.

[0463] Step E: Dissolve tert-butyl (R)-3-(2-((S)-4-benzyl-2-oxooxazolidin-3-yl)-2-oxoethyl)pyrrolidine-1-carboxylate (4.4 g, 11.44 mmol) in dry tetrahydrofuran (5.2 mL) at -30°C under nitrogen. Slowly add 1M lithium bistrimethylsilylamide (13.72 mL, 13.72 mmol) dropwise to the solution and stir for 30 minutes. Then, slowly add a solution of 5-bromo-7-(bromomethyl)-2,3-dihydrobenzo[b][1,4]dioxane (4.2 g, 13.72 mmol) in tetrahydrofuran (7.8 mL) dropwise and stir for 30 minutes. The reaction mixture is stirred at 0°C for 2 hours.

[0464] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was added to an ice-cold saturated ammonium chloride solution (100 mL) for quenching. The mixture was extracted with ethyl acetate (200 mL × 3 times), and the organic phases were combined and washed with saturated brine (200 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 4 g of tert-butyl 3-((S)-1-(S)-4-benzyl-2-oxooxazolidin-3-yl)-3-(8-bromo-2,3-dihydrobenzo[b][1,4]dioxan-6-yl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate.

[0465] MS (ESI) M / Z: 515.1 [M-99] + .

[0466] Step F: In an ice-water bath under nitrogen, tert-butyl 3-((S)-1-(S)-4-benzyl-2-oxooxazolidin-3-yl)-3-(8-bromo-2,3-dihydrobenzo[b][1,4]dioxan-6-yl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (4 g, 6.51 mmol) was dissolved in tetrahydrofuran (32 mL). A 33% aqueous solution of hydrogen peroxide (11 mL, 9.77 mmol) and an aqueous solution of lithium hydroxide monohydrate (430 mg, 9.77 mmol) (9.8 mL) were then slowly added dropwise to the solution. The reaction system was then stirred for 4 hours.

[0467] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched with sodium bisulfite solution (8 mL), adjusted to pH > 12 with saturated sodium hydroxide solution, and extracted with methyl tert-butyl ether (100 mL x 4). The aqueous phase was then adjusted to pH 3 with 8M hydrochloric acid solution and extracted with ethyl acetate (100 mL x 3). The organic phases were combined and washed with saturated brine (50 mL x 2). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield 2.5 g of (S)-3-(8-bromo-2,3-dihydrobenzo[b][1,4]dioxan-6-yl)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)propanoic acid.

[0468] MS (ESI) M / Z: 400.2 [M-55] + .

[0469] Step G: (S)-3-(8-Bromo-2,3-dihydrobenzo[b][1,4]dioxan-6-yl)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)propanoic acid (2.5 g, 5.49 mmol) and 2-tert-butyl-1,3-diisopropylisourea (3.85 g, 19.23 mmol) were dissolved in dry tetrahydrofuran (7 mL) at room temperature under nitrogen. The reaction was then stirred at 65°C for 4 hours.

[0470] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was filtered and quenched with ice water (50 mL). The mixture was extracted with ethyl acetate (60 mL × 3 times), and the organic phases were combined and washed with saturated brine (60 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 2 g of tert-butyl (R)-3-((S)-3-(8-bromo-2,3-dihydrobenzo[b][1,4]dioxan-6-yl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate.

[0471] MS (ESI) M / Z: 456.3 [M-55] +

[0472] Step H: Dissolve tert-butyl (R)-3-((S)-3-(8-bromo-2,3-dihydrobenzo[b][1,4]dioxan-6-yl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (1.8 g, 3.52 mmol), 3-oxobenzo[d]isothiazole-2(3H)-carbaldehyde 1,1-dioxide (1.86 g, 8.8 mmol), palladium acetate (160 mg, 0.7 mmol), 1,4-bis(diphenylphosphino)butane (300 mg, 0.7 mmol), sodium carbonate (1.12 g, 10.56 mmol), and triethylsilane (820 mg, 7.04 mmol) in dry N,N-dimethylformamide (18 mL) at room temperature. The air was evacuated under vacuum three times to replace the atmosphere with nitrogen, and the reaction was stirred at 75°C for 16 hours.

[0473] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was added to ice water (100 mL) to quench the mixture. The mixture was extracted with ethyl acetate (60 mL × 3 times), and the organic phases were combined and washed with saturated brine (40 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 800 mg of tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(8-formyl-2,3-dihydrobenzo[b][1,4]dioxan-6-yl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate.

[0474] MS (ESI) M / Z: 484.2 [M+23] + .

[0475] Step I: Under nitrogen at room temperature, dissolve tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(8-formyl-2,3-dihydrobenzo[b][1,4]dioxan-6-yl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (400 mg, 0.87 mmol) in isopropanol (4.5 mL). Then, add 3.5 M ammonia in isopropanol (0.45 mL, 1.56 mmol) and acetic acid (78 mg, 1.31 mmol) dropwise to the solution and stir for 1 hour. Then, add sodium cyanoborohydride (548 mg, 8.7 mmol), raise the temperature to 70°C, and continue stirring for 4 hours.

[0476] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was added to ice water (100 mL) for quenching. The mixture was extracted with ethyl acetate (60 mL × 3 times), and the organic phases were combined and washed with saturated brine (60 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 250 mg of the compound 3,3'-di-tert-butyl((2S,2'S)-((nitrodiylbis(methylene))bis(2,3-dihydrobenzo[b][1,4]dioxol-8,6-diyl)bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate) and 70 mg of the compound 3,3',3'-((2S,2'S,2'S)-((nitrilotris(methylene))tris(2,3-dihydrobenzo[b][1,4]dioxetine-7,5-diyl))-tris(3-(tert-butoxy)-3-oxopropane-1,2-diyl)(3R,3'R,3'R)-tris(pyrrolidine-1-carboxylate).

[0477] MS (ESI) M / Z: 908.3 [M+H] + .

[0478] MS (ESI) M / Z: 627.4 [(M-100) / 2+H] + .

[0479] Step J: 3,3'-di-tert-butyl((2S,2'S)-((nitrogendiylbis(methylene))bis(2,3-dihydrobenzo[b][1,4]dioxo-8,6-diyl)bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate) (250 mg, 0.27 mmol), (R)-tert-butyl 3-((S)-3-(3-(bromomethyl)phenyl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (155 mg, 0.33 mmol), potassium carbonate (75 mg, 0.54 mmol) and potassium iodide (90 mg, 0.54 mmol) were dissolved in acetonitrile (9 mL) under nitrogen at room temperature. The reaction system was then stirred at 40°C for 5 hours.

[0480] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was added to ice water (50 mL) for quenching. The mixture was extracted with ethyl acetate (60 mL × 3 times), and the organic phases were combined and washed with saturated brine (60 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 240 mg of 3,3'-di-tert-butyl((2S,2'S)-(((3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)benzyl)azinediyl)bis(methylene))bis(2,3-dihydrobenzo[b][1,4]dioxetane-8,6-diyl))bis-(3-(tert-butoxy)-3-oxopropane-1,2-diyl)(3R,3'R)-bis(pyrrolidine-1-carboxylate).

[0481] MS (ESI) M / Z: 598.6 [(M-100) / 2+H] + .

[0482] Step K: 3,3'-di-tert-butyl((2S,2'S)-(((3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)benzyl)azinediyl)bis(methylene))bis(2,3-dihydrobenzo[b][1,4]dioxetane-8,6-diyl))bis-(3-(tert-butoxy)-3-oxopropane-1,2-diyl)(3R,3'R)-bis(pyrrolidine-1-carboxylate) (240 mg, 0.18 mmol) was dissolved in 4M hydrochloric acid-1,4-dioxane (10 mL) at room temperature. The reaction was stirred at room temperature for 4 hours.

[0483] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was filtered, the filter cake was rinsed with dichloromethane (10 mL×2 times), the filter cake was collected, and concentrated under reduced pressure to obtain 72.69 mg of (2S,2'S)-3,3'-(((3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)benzyl)azepinediyl)bis(methylene))bis(2,3-dihydrobenzo[b][1,4]dioxetane-8,6-diyl))bis-(2-(((R)-pyrrolidin-3-yl)propionic acid) hydrochloride.

[0484] MS (ESI) M / Z: 827.4 [M+H] + .

[0485] 1H NMR(400MHz,D2O)δ7.25-7.16(m,2H),6.78(s,2H),6.76-6.65(m,3H),6.61(s,1H),4.36(s,4H),4.29(s,2H),4.22-3.84(m,8H),3.53-3.42( m,3H),3.40-3.29(m,3H),3.24-3.12(m,3H),2.98-2.85(m,3H),2.73- 2.58(m,6H),2.46-2.30(m,6H),2.10-1.98(m,3H),1.75-1.60(m,3H).

[0486] Example 248

[0487] (2S,2'S,2"S)-3,3',3"-((nitrilotris(methylene))tris(2,3-dihydrobenzo[b][1,4]dioxin-8,6-diyl))tris(2-((R)-pyrrolidin-3-yl)propanoic acid)

[0488] It can also be prepared according to the following steps:

[0489] Reaction route:

[0490] Steps:

[0491] Step A: tert-Butyl 3,3',3"-((2S,2'S,2"S)-((nitrilotris(methylene))tris(2,3-dihydrobenzo[b][1,4]dioxetine-7,5-diyl))-tris(3-(tert-butoxy)-3-oxopropane-1,2-diyl)(3R,3'R,3"R)-tris(pyrrolidine-1-carboxylate) (70 mg, 0.05 mmol) was dissolved in dichloromethane (0.5 mL) at room temperature. 4M hydrochloric acid-1,4-dioxane (1.5 mL) was then added dropwise to the solution. The reaction was stirred for 4 hours.

[0492] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was filtered and the residual solid was rinsed with dichloromethane (10 mL × 2 times). The solid was collected and concentrated under reduced pressure to obtain 8.18 mg of (2S,2'S,2"S)-3,3',3"-((nitrilotris(methylene))tris(2,3-dihydrobenzo[b][1,4]dioxin-8,6-diyl))tris(2-((R)-pyrrolidin-3-yl)propanoic acid) hydrochloride.

[0493] MS (ESI) M / Z: 885.4 [M+H] + .

[0494] 1 H NMR(400MHz,D2O)δ6.73(s,3H),6.54(s,3H),4.29(m,6H),4.14(m,12H),3.49-3.39(m,3H),3.38-3.28(m,3H),3 .22-3.11(m,3H),2.90-2.85(m,3H),2.65-2.49(m,6H),2.42-2.25(m,6H),2.09-1.97(m,3H),1.72-1.57(m,3H).

[0495] Example 149

[0496] (2S,2'S)-3,3'-(((4-(4-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)phenyl)piperidin-1-yl)methylene)bis(3,1-phenylene))bis(2-((R)-pyrrolidin-3-yl)propanoic acid)

[0497] It can also be prepared according to the following steps:

[0498] Reaction route:

[0499] Steps:

[0500] Step A: Dissolve (R)-tert-butyl 3-(2-((S)-4-benzyl-2-oxooxazolidin-3-yl)-2-oxoethyl)pyrrolidine-1-carboxylate (3.5 g, 9.0 mmol) in dry tetrahydrofuran (3.6 mL) at -30°C under nitrogen. Slowly add 1M lithium bistrimethylsilylamide (10.8 mL, 10.8 mmol) dropwise to the solution and stir for 30 minutes. Then, slowly add a solution of 1-(bromomethyl)-3-iodobenzene (3.2 g, 10.8 mol) in tetrahydrofuran (5.4 mL) dropwise. Stir for 30 minutes, then warm to 0°C and continue stirring for 2 hours.

[0501] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was poured into an ice-cold saturated ammonium chloride solution (100 mL) for quenching. The mixed solution was extracted with ethyl acetate (200 mL × 3 times), and the organic phases were combined and washed with a saturated aqueous solution of common salt (200 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. 4.5 g of tert-butyl 3-(S)-1-(S)-4-benzyl-2-oxooxazolidin-3-yl)-3-(3-iodophenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate was obtained.

[0502] MS (ESI) M / Z: 627.1 [M+23] + .

[0503] Step B: Dissolve tert-butyl 3-(S)-1-(S)-4-benzyl-2-oxooxazolidin-3-yl)-3-(3-iodophenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (4.3 g, 7.1 mmol) in tetrahydrofuran (47 mL) at 0°C. Then, slowly add a 33% aqueous solution of hydrogen peroxide (1.2 g, 10.65 mmol) in water (12 mL) and a solution of lithium hydroxide monohydrate (447 mg, 10.65 mmol) in water (11 mL) dropwise to the solution. Stir the reaction for 3 hours.

[0504] After LCMS monitoring showed the disappearance of the starting material, sodium bisulfite solution (8 mL) was added to the reaction solution to quench it. The pH was adjusted to >12 with saturated sodium hydroxide aqueous solution and extracted with methyl tert-butyl ether (100 mL × 4 times). The aqueous phase was then adjusted to pH = 3 with 8M hydrochloric acid solution and extracted with ethyl acetate (100 mL × 3 times). The organic phases were combined and washed with saturated brine (50 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 2.5 g of (S)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-(3-iodophenyl)propanoic acid.

[0505] MS (ESI) M / Z: 468.0 [M+23] + .

[0506] Step C: (S)-2-((R)-1-(tert-Butoxycarbonyl)pyrrolidin-3-yl)-3-(3-iodophenyl)propanoic acid (2.3 g, 5.17 mmol) and 2-tert-butyl-1,3-diisopropylisourea (3.6 g, 18.1 mmol) were dissolved in tetrahydrofuran (5.2 mL) at room temperature under nitrogen. The reaction was then stirred at 65°C for 16 hours.

[0507] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was filtered and the filter cake was rinsed with tetrahydrofuran (30 mL x 4). Water (100 mL) was added to the filtrate to quench the mixture, and the mixture was extracted with ethyl acetate (50 mL x 3 times). The organic phases were combined and washed with saturated aqueous sodium chloride solution (50 mL x 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 2.2 g of tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(3-iodophenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate.

[0508] MS (ESI) M / Z: 524.1 [M+23] + .

[0509] Step D: At 0°C under nitrogen, dissolve tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(3-iodophenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (600 mg, 1.2 mmol) in dry tetrahydrofuran (2.4 mL). Then, slowly add 2M lithium isopropylmagnesium chloride solution (1.2 mL, 2.4 mmol) dropwise to the solution. Then, slowly add a solution of tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(3-formylphenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (482 mg, 1.2 mol) in tetrahydrofuran (0.5 mL) dropwise, warm to room temperature, and stir for 1 hour.

[0510] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched with water (30 mL). The mixture was extracted with ethyl acetate (20 mL x 3 times), and the organic phases were combined and washed with saturated sodium chloride solution (80 mL x 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 400 mg of 3,3'-((2S,2'S)-((hydroxymethylene)bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate).

[0511] Step E: 3,3'-((2S,2'S)-((hydroxymethylene)bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate) (330 mg, 0.42 mmol) was dissolved in dichloromethane (4 mL) at 0°C under nitrogen. Triethylamine (0.1 mL, 0.75 mmol) and methanesulfonyl chloride (62 mg, 0.55 mmol) were then slowly added dropwise to the solution. The reaction was stirred at room temperature for 16 hours.

[0512] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched with water (30 mL). The mixture was extracted with dichloromethane (10 mL x 3 times), and the organic phases were combined and washed with saturated sodium chloride solution (30 mL x 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 56 mg of 3,3'-((2S,2'S)-((chloromethylene)bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate).

[0513] 1H NMR(400MHz,DMSO-d6)δ7.33-7.21(m,6H),7.20-7.09(m,2H),6.39(s,1H),3.57-3.43(m,2H),3.40-3.32(m,2H),3.23-3.07(m,2H),3.03-2.93 (m,2H),2.82-2.64(m,4H),2.59-2.51(m,2H),2.35-2.19(m,2H),1.89- 1.77(m,2H),1.66-1.51(m,2H),1.39(s,18H),1.18(s,9H),1.17(s,9H).

[0514] Step F: 3,3'-((2S,2'S)-((chloromethylene)bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate) (46 mg, 0.06 mmol), (R)-tert-butyl 3-((S)-1-(tert-butoxy)-1-oxo-3-(4-(piperidin-4-yl)phenyl)propan-2-yl)pyrrolidine-1-carboxylate (26 mg, 0.06 mmol), potassium carbonate (16 mg, 0.12 mmol), and potassium iodide (19 mg, 0.12 mmol) were dissolved in acetonitrile (2 mL) at room temperature under nitrogen. The reaction system was then stirred at 40°C for 3 hours.

[0515] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was slowly added to an ice-water solution (40 mL) to quench the reaction. The mixture was extracted with ethyl acetate (20 mL × 3 times), and the organic phases were combined and washed with saturated brine (20 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 16 mg of 3,3'-di-tert-butyl((2S,2'S)-((4-(4-(((S)-3-(tert-butyloxy)-2-((R)-1-(tert-butyloxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)piperidin-1-yl)methylene)bis(3,1-phenylene))bis(3-(tert-butyloxy)-3-oxypropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate).

[0516] MS (ESI) M / Z: 560.5 [(M-100) / 2+H] + .

[0517] Step G: 3,3'-di-tert-butyl((2S,2'S)-((4-(4-(((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)piperidin-1-yl)methylene)bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxypropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate) (16 mg, 0.014 mmol) was dissolved in dry dichloromethane (1 mL) at room temperature. 4M hydrochloric acid-1,4-dioxane (1 mL) was then slowly added dropwise to the solution. The reaction was stirred at room temperature for 16 hours.

[0518] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was filtered and the filter cake was rinsed with dichloromethane (10 mL x 2). The resulting filter cake was lyophilized to obtain 8.01 mg of (2S,2'S)-3,3'-(((4-(4-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)phenyl)piperidin-1-yl)methylene)bis(3,1-phenylene))bis(2-((R)-pyrrolidin-3-yl)propanoic acid) hydrochloride.

[0519] MS (ESI) M / Z: 751.5 [M+H] + .

[0520] 1 H NMR(400MHz,D2O)δ7.51-7.32(m,6H),7.30-7.11(m,6H),5.28(s,1H),3.60-3.49(m,3H),3.48-3.30(m,5H),3.27-3.14(m,3H),3. 12-2.96(m,5H),2.95-2.74(m,7H),2.72-2.61(m,3H),2.57-2.42(m,3H),2.20-2.07(m,3H),2.06-1.85(m,4H),1.78-1.63(m,3H).

[0521] Example 10

[0522] (2S,2'S)-3,3'-(8-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)-2,3-dihydrobenzo[b][1,4]dioxan-6-yl)methyl)nitrogendiyl)bis(methylene))bis(3,1-phenylene)bis(2-(R)pyrrolidin-3-yl)propanoic acid)

[0523] The synthesis of Example 10 refers to Example 11.

[0524] MS (ESI) M / Z: 769.4 [M+H] + .

[0525] 1 H NMR(400MHz,D2O)δ7.45-7.23(m,4H),7.21-7.00(m,4H),6.63(s,2H),4.35-4.00(m,10H),3.65-3.47(m,3H),3.43-3.28( m,3H),3.26-3.12(m,3H),3.09-2.95(m,3H),2.93-2.62(m,9H),2.58-2.43(m,3H),2.18-1.97(m,3H),1.78-1.56(m,3H).

[0526] Example 27

[0527] (2S,2'S)-3,3'-(((3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)benzyl)azinediyl)bis(methylene)bis(2,3-dihydro-1H-inden-6,4-yl))bis-(2-((R)-pyrrolidin-3-yl)propanoic acid)

[0528] It can also be prepared according to the following steps:

[0529] Reaction route:

[0530] Steps:

[0531] Step A: Dissolve N-(2,3-dihydro-1H-inden-5-yl)acetamide (20 g, 114.3 mmol) in acetic acid (300 mL) in an ice-water bath. Then, slowly add liquid bromine (24 g, 150 mmol) dropwise to the solution. The reaction mixture is stirred at 4-5°C for 1 hour.

[0532] After TLC monitoring showed the disappearance of the starting material, the mixture was added to an ice-cold saturated ammonium chloride solution (1000 mL) for quenching. The mixture was extracted with ethyl acetate (300 mL x 3), and the organic phases were combined and washed with saturated brine (200 mL x 2). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. 23 g of crude N-(6-bromo-2,3-dihydro-1H-inden-5-yl)acetamide was obtained.

[0533] 1 H NMR (400MHz, DMSO-d6) δ9.36(s,1H),7.47(s,1H),7.37(s,1H),2.91-2.75(m,4H),2.12-2.00(m,5H).

[0534] Step B: Dissolve N-(6-bromo-2,3-dihydro-1H-inden-5-yl)acetamide (23 g, 90.9 mmol) in concentrated hydrochloric acid / ethanol (100 mL / 100 mL) at room temperature, and then stir the reaction system at 90°C for 3 hours.

[0535] After TLC monitoring showed the disappearance of the starting material, the mixture was quenched with 10% aqueous sodium hydroxide solution (1000 mL). The mixture was extracted with dichloromethane (300 mL x 2), and the organic phases were combined and washed with saturated brine (200 mL x 2). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. 16 g of crude product, 6-bromo-2,3-dihydro-1H-inden-5-amine, was obtained.

[0536] 1 H NMR (400MHz, DMSO-d6) δ7.16(s,1H),6.67(s,1H),4.99(s,2H),2.75-2.64(m,4H),1.98-1.87(m,2H).

[0537] Step C: Dissolve 6-bromo-2,3-dihydro-1H-indene-5-amine (12 g, 56.87 mmol) in acetic acid (240 mL) in an ice-water bath. Add N-iodosuccinimide (19.2 g, 85.31 mmol) to the solution. Stir the reaction at room temperature for 16 hours.

[0538] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was added to ice water (100 mL) for quenching. The mixture was extracted with dichloromethane (200 mL × 3 times), and the organic phases were combined and washed with saturated brine (200 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 14 g of 6-bromo-4-iodo-2,3-dihydro-1H-inden-5-amine.

[0539] MS (ESI) M / Z: 338.0 [M+H] + .

[0540] Step D: Dissolve 6-bromo-4-iodo-2,3-dihydro-1H-inden-5-amine (14 g, 41.54 mmol) in dry tetrahydrofuran (180 mL) at 0°C. Then, slowly add boron trifluoride-ether solution (7.83 g, 76.02 mmol) dropwise to the solution and stir for 5 minutes. Then, add isoamyl nitrite (7.8 g, 66.46 mmol), stir for 1 hour, warm to room temperature, and continue stirring for 16 hours.

[0541] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was concentrated under reduced pressure. The resulting residue was slurried with methyl tert-butyl ether (40 mL), filtered, and the solid was collected and dried in vacuo to obtain 15 g of 6-bromo-4-iodo-2,3-dihydro-1H-indene-5-diazonium.

[0542] MS (ESI) M / Z: 350.8 [M] + .

[0543] Step E: Dissolve 6-bromo-4-iodo-2,3-dihydro-1H-indene-5-diazonium (15 g, 42.98 mmol) in N,N-dimethylformamide (215 mL) in an ice-water bath. Then, add ferrous sulfate heptahydrate (14.4 g, 51.58 mmol). The reaction mixture is stirred at room temperature for 2 hours.

[0544] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was added to ice water (1000 mL) for quenching. The mixture was extracted with ethyl acetate (300 mL x 3), and the organic phases were combined and washed with saturated brine (600 mL x 2). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 11 g of 6-bromo-4-iodo-2,3-dihydro-1H-indene.

[0545] 1 H NMR (400MHz, DMSO-d6) δ7.69(s,1H),7.43(s,1H),3.02(t,J=7.6Hz,2H),2.76(t,J=7.6Hz,2H),2.07-1.94(m,2H).

[0546] Step F: In an ice-water bath under nitrogen, dissolve 6-bromo-4-iodo-2,3-dihydro-1H-indene (11 g, 34.16 mmol) in dry tetrahydrofuran (48 mL). Slowly add 2M isopropylmagnesium chloride solution (20 mL, 40.99 mmol) dropwise to the solution, warm to room temperature, and stir for 1 hour. Then, slowly add N,N-dimethylformamide (4.99 g, 68.32 mmol) dropwise and continue stirring for 1 hour.

[0547] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was added to ice water (100 mL) for quenching. The mixture was extracted with ethyl acetate (100 mL x 3), and the organic phases were combined and washed with saturated brine (200 mL x 2). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 7 g of 6-bromo-2,3-dihydro-1H-indene-4-carbaldehyde.

[0548] MS (ESI) M / Z: 224.9 [M+H] + .

[0549] Step G: In an ice-water bath under nitrogen, dissolve 6-bromo-2,3-dihydro-1H-indene-4-carbaldehyde (7 g, 31.25 mmol) in methanol (156 mL). Then, slowly add sodium borohydride (1.8 g, 46.88 mmol) to the solution. The reaction mixture is stirred at room temperature for 1 hour.

[0550] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was concentrated under reduced pressure, and the resulting residue was quenched with ice water (100 mL). The mixture was extracted with ethyl acetate (60 mL × 3 times), and the organic phases were combined and washed with saturated brine (100 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. 6.5 g of (6-bromo-2,3-dihydro-1H-inden-4-yl)methanol was obtained.

[0551] MS (ESI) M / Z: 209.0 [M-17] + .

[0552] Step H: In an ice-water bath under nitrogen, dissolve (6-bromo-2,3-dihydro-1H-inden-4-yl)methanol (6.5 g, 28.76 mmol) in dichloromethane (144 mL). Then, slowly add phosphorus tribromide (11.7 g, 43.14 mmol) dropwise to the solution. The reaction mixture is stirred at room temperature for 4 hours.

[0553] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was quenched by adding ice water (100 mL). The mixture was extracted with ethyl acetate (200 mL x 3), and the organic phases were combined and washed with saturated brine (200 mL x 2). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 7 g of 6-bromo-4-(bromomethyl)-2,3-dihydro-1H-indene.

[0554] Step I: Dissolve (R)-tert-butyl 3-(2-((S)-4-benzyl-2-oxooxazolidin-3-yl)-2-oxoethyl)pyrrolidine-1-carboxylate (5 g, 13.02 mmol) in dry tetrahydrofuran (6.3 mL) at -30°C under nitrogen. Slowly add 1M lithium bistrimethylsilylamide (15.63 mL, 15.63 mmol) dropwise to the solution and stir for 30 minutes. Then, slowly add a solution of 6-bromo-4-(bromomethyl)-2,3-dihydro-1H-indene (4.5 g, 15.63 mmol) in tetrahydrofuran (9.5 mL) dropwise and continue stirring for 1 hour. Then, warm the reaction mixture to room temperature and continue stirring for 2 hours.

[0555] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was added to an ice-cold saturated ammonium chloride solution (50 mL) to quench the mixture. The mixture was extracted with ethyl acetate (20 mL × 3 times), and the organic phases were combined and washed with saturated brine (20 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. This yielded 6 g of (R)-3-((S)-1-(S)-4-benzyl-2-oxooxazolidin-3-yl)-3-(6-bromo-2,3-dihydro-1H-inden-4-yl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester.

[0556] MS (ESI) M / Z: 619.2 [M+23] + .

[0557] Step J: In an ice-water bath, tert-butyl (R)-3-((S)-1-(S)-4-benzyl-2-oxooxazolidin-3-yl)-3-(6-bromo-2,3-dihydro-1H-inden-4-yl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (6 g, 10.07 mmol) was dissolved in tetrahydrofuran (67 mL). A solution of lithium hydroxide monohydrate (634 mg, 15.1 mmol) in water (15.1 mL) and a solution of 33 wt% hydrogen peroxide (17.2 mL, 15.1 mmol) in water were slowly added dropwise to the solution. The reaction system was then stirred for 4 hours.

[0558] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched by the addition of saturated sodium bisulfite solution (8 mL). The pH was adjusted to >12 with saturated sodium hydroxide solution, and the mixture was extracted with methyl tert-butyl ether (100 mL x 4). The aqueous phase was then adjusted to pH 3 with 8M hydrochloric acid solution and extracted with ethyl acetate (100 mL x 3). The organic phases were combined and washed with saturated brine (50 mL x 2). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield 3.5 g of (S)-3-(6-bromo-2,3-dihydro-1H-inden-4-yl)-2-(R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)propanoic acid.

[0559] MS (ESI) M / Z: 382.0 [M-55] + .

[0560] Step K: (S)-3-(6-bromo-2,3-dihydro-1H-inden-4-yl)-2-(R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)propanoic acid (3.5 g, 8.01 mmol) and tert-butyl N,N-diisopropylcarbamate (5.6 g, 28.03 mmol) were dissolved in dry tetrahydrofuran (10 mL) under nitrogen at room temperature. The reaction was stirred at 65°C for 5 hours.

[0561] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was filtered and the filter cake was rinsed with tetrahydrofuran (50 mL x 4). The filtrate was quenched with water (100 mL) and extracted with ethyl acetate (60 mL x 3). The organic phases were combined and washed with saturated brine (60 mL x 2). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 3.2 g of tert-butyl (R)-3-((S)-3-(6-bromo-2,3-dihydro-1H-inden-4-yl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate.

[0562] MS (ESI) M / Z: 516.2 [M+23] +

[0563] Step L: Dissolve tert-butyl (R)-3-((S)-3-(6-bromo-2,3-dihydro-1H-inden-4-yl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (600 mg, 1.22 mmol), 3-oxobenzo[d]isothiazole-2(3H)-carbaldehyde 1,1-dioxide (642 mg, 3.04 mmol), palladium acetate (55 mg, 0.25 mmol), 1,4-bis(diphenylphosphino)butane (104 mg, 0.25 mmol), sodium carbonate (388 mg, 3.66 mmol), and triethylsilane (283 mg, 2.44 mmol) in N,N-dimethylformamide (6.1 mL) at room temperature. Evacuate the air and replace with nitrogen three times. Stir the reaction at 75°C for 16 hours.

[0564] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was added to ice water (100 mL) to quench the mixture. The mixture was extracted with ethyl acetate (30 mL × 3 times), and the organic phases were combined and washed with saturated brine (40 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 350 mg of tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(6-formyl-2,3-dihydro-1H-inden-4-yl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate.

[0565] MS (ESI) M / Z: 466.2 [M+23] + .

[0566] Step M: At room temperature under nitrogen, dissolve tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(6-formyl-2,3-dihydro-1H-inden-4-yl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (350 mg, 0.79 mmol) in isopropanol (4 mL). Then, add 3.5 M ammonia in isopropanol (0.4 mL, 1.42 mmol) and acetic acid (71 mg, 1.19 mmol) dropwise to the solution and stir for 1 hour. Then, add sodium cyanoborohydride (498 mg, 7.9 mmol), raise the temperature to 70°C, and continue stirring for 4 hours.

[0567] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was added to ice water (100 mL) for quenching. The mixture was extracted with ethyl acetate (60 mL × 3 times), and the organic phases were combined and washed with saturated brine (60 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 100 mg of 3,3',3'-((2S,2'S,2'S)-((nitrilotris(methylene))tris(2,3-dihydro-1H-indene-6,4-diyl))-tris(3-(tert-butoxy)-3-oxopropane-1,2-diyl)(3R,3'R,3'R)-tris(pyrrolidine-1-carboxylate) and 120 mg of 3,3'-((2S,2'S)-((azadiylbis(methylene))bis(2,3-dihydro-1H-indene-6,4-diyl))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl)(3R,3'R)-bis(pyrrolidine-1-carboxylate).

[0568] MS (ESI) M / Z: 872.5 [M+H] +

[0569] Step N: 3,3'-((2S,2'S)-((azadiylbis(methylene))bis(2,3-dihydro-1H-indene-6,4-diyl))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl)(3R,3'R)-bis(pyrrolidine-1-carboxylate) (120 mg, 0.14 mmol), (R)-tert-butyl 3-((S)-3-(3-(bromomethyl)phenyl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (77 mg, 0.17 mmol), potassium carbonate (39 mg, 0.28 mmol), and potassium iodide (47 mg, 0.28 mmol) were dissolved in acetonitrile (4.7 mL) at room temperature. The reaction was stirred at 40°C for 5 hours.

[0570] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched by adding ice water (100 mL). The mixture was extracted with ethyl acetate (30 mL x 3), and the organic phases were combined and washed with saturated brine (30 mL x 2). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 100 mg of 3,3'-di-tert-butyl((2S,2'S)-(((S)-3-(tert-butyloxy)-2-((R)-1-(tert-butyloxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)benzyl)azinediyl)bis(methylene))bis(2,3-dihydro-1H-indene-6,4-diyl))bis-(3-(tert-butyloxy)-3-oxopropane-1,2-diyl)(3R,3'R)-bis(pyrrolidine-1-carboxylate).

[0571] MS (ESI) M / Z: 580.5 [(M-100) / 2+H] + .

[0572] Step O: 3,3'-di-tert-butyl((2S,2'S)-(((3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)benzyl)azinediyl)bis(methylene))bis(2,3-dihydro-1H-indene-6,4-diyl))bis-(3-(tert-butoxy)-3-oxopropane-1,2-diyl)(3R,3'R)-bis(pyrrolidine-1-carboxylate) (100 mg, 0.08 mmol) was dissolved in 4M hydrochloric acid-1,4-dioxane (2 mL) under nitrogen at room temperature. The reaction system was then stirred for 4 hours.

[0573] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was filtered, and the resulting residual solid was rinsed with dichloromethane (10 mL x 2). The filter cake was purified by preparative HPLC (0.1% aqueous HCl / acetonitrile) and lyophilized to obtain 50.77 mg of (2S,2'S)-3,3'-(((3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)benzyl)azinediyl)bis(methylene)bis(2,3-dihydro-1H-inden-6,4-yl))bis-(2-((R)-pyrrolidin-3-yl)propanoic acid) hydrochloride.

[0574] MS (ESI) M / Z: 791.4 [M+H] + .

[0575] 1H NMR(400MHz,D2O)δ7.35-7.27(m,2H),7.12-7.07(m,2H),6.92(s,2H),6. 81(s,2H),4.35-4.08(m,6H),3.63-3.51(m,3H),3.44-3.32(m,3H),3.27- 3.15(m,3H),3.06-2.95(m,3H),2.93-2.73(m,14H),2.72-2.60(m,3H),2. 59-2.44(m,3H),2.19-2.06(m,3H),2.05-1.88(m,4H),1.82-1.58(m,3H).

[0576] Example 25

[0577] (2S,2'S)-3,3'-(((3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)benzyl)nitrogendiyl)bis(methylene)bis(2,3-dihydro-1H-indene-7,5-diyl))bis(2-(((R)-pyrrolidin-3-yl)propanoic acid

[0578] The synthesis of Example 25 refers to Example 27.

[0579] MS (ESI) M / Z: 791.5 [M+H] + .

[0580] 1 H NMR(400MHz,D2O)δ7.39-7.31(m,2H),7.26-7.19(m,2H),7.17(s,2H),6.95(s ,2H),4.40-4.42(m,2H),4.29-4.19(m,4H),3.64-3.49(m,3H),3.45-3.31(m,3 H),3.28-3.13(m,3H),3.11-2.97(m,3H),2.94-2.63(m,13H),2.60-2.45(m,3H ),2.44-2.27(m,4H),2.20-2.04(m,3H),1.94-1.81(m,4H),1.77-1.62(m,3H).

[0581] Example 28

[0582] (2S,2'S,2'S)-3,3'-((nitrilotris(methylene))tris(2,3-dihydro-1H-indene-7,5-diyl))tris(2-(((R)-pyrrolidin-3-yl)propanoic acid)

[0583] The synthesis of Example 28 was carried out with reference to Example 27.

[0584] MS (ESI) M / Z: 831.5 [M+H] + .

[0585] 1 H NMR(400MHz,D2O)δ7.20(s,3H),6.99(s,3H),4.36-4.29(m,6H),3.60-3.51(m,3H),3.41-3.33(m,3H),3.25-3.15(m,3H),3.04-2.98(m,3 H),2.89-2.72(m,12H),2.68-2.59(m,3H),2.56-2.43(m,3H),2.31-2.27(m,6H),2.15-2.05(m,3H),1.94-1.80(m,6H),1.76-1.64(m,3H).

[0586] Example 29

[0587] (2S,2'S,2'S)-3,3',3'-((nitrilotris(methylene))tris(2,3-dihydro-1H-indene-6,4-diyl))tris(2-(((R)-pyrrolidin-3-yl)propanoic acid)

[0588] The synthesis of Example 29 was carried out with reference to Example 27.

[0589] MS (ESI) M / Z: 831.4 [M+H] + .

[0590] 1 H NMR(400MHz,D2O)δ6.88(s,3H),6.80(s,3H),4.22-4.14(m,6H),3.59-3.54(m,3H),3.45-3.33(m,3H),3.28-3.15(m,3H),3.06- 2.95(m,3H),2.89-2.73(m,18H),2.72-2.62(m,3H),2.61-2.48(m,3H),2.18-2.08(m,3H),2.06-1.89(m,6H),1.78-1.64(m,3H).

[0591] Example 132

[0592] (2S,2'S)-3,3'-((((3-(3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)phenyl)cyclobutyl)azinediyl)bis(methylene))bis(3,1-phenylene))bis(2-((R)-pyrrolidin-3-yl)propanoic acid

[0593] It can also be prepared according to the following steps:

[0594] Reaction route:

[0595] Steps:

[0596] Step A: Dissolve 3-aminocyclobutane-1-ol (3.8 g, 43.5 mmol) and benzyl(2,5-dioxopyrrolidin-1-yl) carbonate (12 g, 47.9 mmol) in dichloromethane (106 mL) at room temperature. Then, add triethylamine (8.8 g, 87 mmol) dropwise to the solution. Stir the reaction for 2 hours.

[0597] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was slowly added to ice water (200 mL) to quench the reaction. The mixture was extracted with dichloromethane (100 mL × 3 times), and the organic phases were combined and washed with saturated brine (300 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified on a silica gel column to obtain 4.5 g of benzyl (3-hydroxycyclobutyl) carbamate.

[0598] MS (ESI) M / Z: 222.2 [M+H] + .

[0599] Step B: Dissolve benzyl (3-hydroxycyclobutyl) carbamate (4.5 g, 20.25 mmol) in toluene (67 mL) at room temperature under nitrogen. Add imidazole (4.1 g, 60.75 mmol), triphenylphosphine (10.6 g, 40.5 mmol), and iodine (7.7 g, 30.37 mmol) sequentially to the solution. Stir the reaction at 100°C for 2 hours.

[0600] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was slowly added to ice water (100 mL) to quench the reaction. The mixture was extracted with ethyl acetate (100 mL × 3 times), and the organic phases were combined and washed with saturated brine (100 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified on a silica gel column to yield 5.4 g of benzyl (3-iodocyclobutyl) carbamate.

[0601] MS (ESI) M / Z: 354.0 [M+23]+ .

[0602] Step C: At room temperature, under nitrogen, add zinc powder (600 mg, 9.42 mmol) to N,N-dimethylacetamide (3 mL). Subsequently, add 1,2-dibromoethane (202 mg, 1.08 mmol) to the solution, heat to 80°C, and stir for 10 minutes. Then, cool to room temperature and stir for 5 minutes. Repeat this process twice. Add trimethylsilyl chloride (200 mg, 1.84 mmol) and stir for 5 minutes. Then, cool the reaction mixture to 0°C, add benzyl (3-iodocyclobutyl) carbamate (1 g, 3.02 mmol), warm to room temperature, and stir for 1 hour to obtain a solution of (3-((benzyloxy)carbonyl)amino)cyclobutyl)zinc iodide in N,N-dimethylacetamide. Set aside for further use.

[0603] Step D: At room temperature, under nitrogen, tert-butyl (R)-3-((S)-3-(3-bromophenyl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (684 mg, 1.5 mmol) and tetrakis(triphenylphosphine)palladium (173 mg, 0.15 mmol) were dissolved in N,N-dimethylacetamide (1.5 mL). The prepared solution of (3-((benzyloxy)carbonyl)amino)cyclobutyl)zinc iodide in N,N-dimethylacetamide was then added dropwise. The reaction system was stirred at 100°C for 7 hours.

[0604] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was slowly added to ice water (30 mL) to quench the reaction. The mixed solution was extracted with ethyl acetate (10 mL × 3 times), and the organic phases were combined and washed with saturated brine (30 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column to obtain 115 mg of tert-butyl (R)-3-((S)-3-(3-(((benzyloxy)carbonyl)amino)cyclobutyl)phenyl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate.

[0605] MS (ESI) M / Z: 601.3 [M+23] + .

[0606] Step E: Tert-butyl (R)-3-((S)-3-(3-(((benzyloxy)carbonyl)amino)cyclobutyl)phenyl)-1-(tert-butyloxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (115 mg, 0.2 mmol) was dissolved in isopropanol (5 mL) at room temperature. 10 wt% palladium on carbon (23 mg) was then added to the solution. The hydrogen atmosphere was replaced by vacuum evacuation three times, and the reaction was stirred at room temperature for 16 hours.

[0607] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was filtered and concentrated under reduced pressure to obtain 32 mg of tert-butyl (R)-3-((S)-3-(3-(3-aminocyclobutyl)phenyl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate.

[0608] MS (ESI) M / Z: 445.3 [M+H] + .

[0609] Step F: (R)-tert-Butyl 3-((S)-3-(3-(3-aminocyclobutyl)phenyl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (32 mg, 0.07 mmol), (R)-tert-Butyl 3-((S)-3-(3-(bromomethyl)phenyl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (70 mg, 0.15 mmol), potassium carbonate (20 mg, 0.14 mmol), and potassium iodide (24 mg, 0.14 mmol) were dissolved in acetonitrile (2.5 mL) at room temperature under nitrogen. The reaction was then stirred at 45°C for 3 hours.

[0610] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was slowly added to an ice-water solution (20 mL) to quench the reaction. The mixture was extracted with ethyl acetate (10 mL x 3), and the organic phases were combined and washed with saturated brine (30 mL x 2). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by reverse-phase column chromatography to obtain 61 mg of 3,3'-di-tert-butyl((2S,2'S)-(((3-(3-(((S)-3-(tert-butyloxy)-2-((R)-1-(tert-butyloxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)cyclobutyl)azinediyl)bis(methylene))bis(3,1-phenylene)bis(3-(tert-butyloxy)-3-hydroxypropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate).

[0611] MS (ESI) M / Z: 560.4 [(M-100) / 2+H] + .

[0612] Step G: 3,3'-di-tert-butyl((2S,2'S)-(((3-(3-(((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)cyclobutyl)azinediyl)bis(methylene))bis(3,1-phenylene)bis(3-(tert-butoxy)-3-hydroxypropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate) (61 mg, 0.05 mmol) was dissolved in dry dichloromethane (2.5 mL) at room temperature. 4M hydrochloric acid-1,4-dioxane (1.25 mL) was then slowly added dropwise to the solution. The reaction was stirred for 16 hours.

[0613] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was filtered and the filter cake was rinsed with dichloromethane (10 mL x 2). The resulting filter cake was purified by preparative HPLC (0.1% aqueous HCl / acetonitrile) and lyophilized to obtain 35 mg of (2S,2'S)-3,3'-((((3-(3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)phenyl)cyclobutyl)azinediyl)bis(methylene))bis(3,1-phenylene))bis(2-((R)-pyrrolidin-3-yl)propanoic acid hydrochloride (isomer ratio approximately 1:1).

[0614] MS (ESI) M / Z: 751.5 [M+H] + .

[0615] 1 H NMR(400MHz,D2O)δ7.49-6.94(m,12H),4.32-4.08(m,4H),4.07-3.96(m,0.5H),3.91-3.77(m,0.5H),3.63-3.49(m,3H),3.49-3.32(m,3.5H ),3.28-3.10(m,3.5H),3.09-2.96(m,3H),2.96-2.61(m,10H),2.59- 2.38(m,4H),2.36-2.22(m,1H),2.20-2.04(m,4H),1.81-1.62(m,3H).

[0616] Example 134

[0617] (2S,2'S)-3,3'-(((4-(4-((S)-2-carboxy-2-(((R)-pyrrolidin-3-yl)ethyl)phenyl)cyclohexyl)azinediyl)bis(methylene)bis(3,1-phenylene))bis(2-(((R)-pyrrolidin-3-yl)propanoic acid)

[0618] It can also be prepared according to the following steps:

[0619] Reaction route:

[0620] Steps:

[0621] Step A: Dissolve tert-butyl (R)-3-((S)-3-(4-bromophenyl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (1.5 g, 3.30 mmol) in 1,4-dioxane / water (16.5 mL / 1.8 mL) at 0°C under nitrogen. Then, add tert-butyldimethyl((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-yl)oxy)silane (1.45 g, 4.29 mmol), sodium carbonate (1.05 g, 9.90 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (269 mg, 0.33 mmol) in the resulting solution. The air was evacuated under vacuum and replaced with nitrogen three times, and the reaction system was stirred at 100°C for 16 hours.

[0622] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was filtered and the filter cake was rinsed with ethyl acetate (30 mL x 2). The filtrate was quenched with water (40 mL), and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined and washed with saturated sodium chloride solution (30 mL x 2). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 1.32 g of tert-butyl (3R)-3-((2S)-1-(tert-butyloxy)-3-(4'-((tert-butyldimethylsilyl)oxy)-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-yl)-1-oxopropyl-2-yl)pyrrolidine-1-carboxylate.

[0623] Step B: Tert-butyl (3R)-3-((2S)-1-(tert-butoxy)-3-(4'-((tert-butyldimethylsilyl)oxy)-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-yl)-1-oxopropyl-2-yl)pyrrolidine-1-carboxylate (1.56 g, 2.66 mmol) and 10 wt% palladium on carbon (312 mg) were dissolved in methanol (20 mL) at room temperature. The hydrogen atmosphere was replaced by air under vacuum three times, and the reaction system was stirred at room temperature for 16 hours.

[0624] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was filtered, the filter cake was rinsed with tetrahydrofuran (80 mL×4 times), all the filtrate was collected and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give 990 mg of tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(4-(4-((tert-butyldimethylsilyl)oxy)cyclohexyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate.

[0625] 1 H NMR (400MHz, CDCl3) δ7.12(d,J=8.0Hz,2H),7.07(d,J=8.0Hz,2H),4.04(brs,1H),3.71-3.58(m,1H),3.55-3.42(m,1H),3.31-3.19 (m,1H),3.00(t,J=9.8Hz,1H),2.83-2.73(m,2H),2.50-2.33(m,3H),2.01-1.84(m,3H),1.83-1.71(m,2H),1.70-1.61(m,1H),1.59 -1.51(m,4H),1.47(s,9H),1.26(s,9H),0.92(s,9H),0.05(s,6H).

[0626] Step C: Tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(4-(4-((tert-butyldimethylsilyl)oxy)cyclohexyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (990 mg, 1.77 mmol) was dissolved in dry tetrahydrofuran (11.2 mL) at 0°C under nitrogen. A 1 M solution of tetrabutylammonium fluoride in 1,4-dioxane (2 mL) was then slowly added dropwise to the solution. The reaction was stirred at room temperature for 16 hours.

[0627] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was added to ice water (100 mL) to quench the reaction. The mixture was extracted with ethyl acetate (50 mL × 3 times), and the organic phases were combined and washed with saturated brine (40 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified on a silica gel column to obtain 320 mg of tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(4-(4-hydroxycyclohexyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate.

[0628] Step D: Tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(4-(4-hydroxycyclohexyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (300 mg, 0.63 mmol) was dissolved in dry dichloromethane (3.2 mL) at 0°C under nitrogen. Dess-Martin periodinane (404 mg, 0.95 mmol) was then added to the solution. The reaction was stirred at room temperature for 1.5 hours.

[0629] After LCMS monitoring showed that the starting material disappeared, the reaction solution was slowly added to ice water (50 mL) to quench. The mixed solution was extracted with ethyl acetate (30 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (30 mL × 2 times). Then it was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column to obtain 274 mg of tert-butyl (R)-3-((S)-1-(tert-butoxy)-1-oxo-3-(4-(4-oxocyclohexyl)phenyl)propan-2-yl)pyrrolidine-1-carboxylate.

[0630] MS (ESI) M / Z: 372.2 [M-99] + .

[0631] Step E: Dissolve tert-butyl (R)-3-((S)-1-(tert-butoxy)-1-oxo-3-(4-(4-oxocyclohexyl)phenyl)propan-2-yl)pyrrolidine-1-carboxylate (250 mg, 0.53 mmol) in methanol / dichloromethane (4.4 mL / 0.9 mL) at room temperature under nitrogen. Then, add ammonium acetate (410 mg, 5.31 mmol) and sodium cyanoborohydride (33 mg, 0.53 mmol) sequentially. The reaction mixture is stirred at 40°C for 1 hour.

[0632] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was added to ice water (40 mL) to quench the reaction. The mixed solution was extracted with ethyl acetate (30 mL × 3 times), and the organic phases were combined and washed with saturated brine (30 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified on a silica gel column to obtain 110 mg of tert-butyl (R)-3-((S)-3-(4-(4-aminocyclohexyl)phenyl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate.

[0633] MS (ESI) M / Z: 473.3 [M+H] + .

[0634] Step F: Tert-butyl (R)-3-((S)-3-(4-(4-aminocyclohexyl)phenyl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (100 mg, 0.21 mmol), tert-butyl (R)-3-((S)-3-(3-(bromomethyl)phenyl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (247 mg, 0.53 mmol), potassium carbonate (59 mg, 0.42 mmol), and potassium iodide (88 mg, 0.53 mmol) were dissolved in acetonitrile (7 mL) at room temperature under nitrogen. The reaction was then stirred at 40°C for 3 hours.

[0635] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was slowly added to ice water (40 mL) to quench the reaction. The mixture was extracted with ethyl acetate (20 mL × 3 times), and the organic phases were combined and washed with saturated brine (20 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column to obtain 127 mg of di-tert-butyl 3,3'-((2S,2'S)-(((4-(4-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenylcyclohexyl)azepinediyl)bis(methylene)bis(3,1-phenyl)bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl)(3R,3'R)-bis(pyrrolidine-1-carboxylic acid).

[0636] Step G: Di-tert-butyl 3,3'-((2S,2'S)-(((4-(4-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenylcyclohexyl)azepinediyl)bis(methylene)bis(3,1-phenyl)bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl)(3R,3'R)-bis(pyrrolidine-1-carboxylic acid) (127 mg, 0.10 mmol) was dissolved in dry dichloromethane (2 mL) at room temperature. Subsequently, 4 M hydrochloric acid-1,4-dioxane (1.35 mL) was slowly added dropwise to the above solution. The reaction system was then stirred at room temperature for 16 hours.

[0637] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was filtered and the filter cake was rinsed with dichloromethane (10 mL x 2). The resulting filter cake was purified by preparative HPLC (0.1% aqueous HCl / acetonitrile) and lyophilized to obtain 112 mg of (2S,2'S)-3,3'-(((4-(4-((S)-2-carboxy-2-(((R)-pyrrolidin-3-yl)ethyl)phenyl)cyclohexyl)azinediyl)bis(methylene)bis(3,1-phenylene))bis(2-(((R)-pyrrolidin-3-yl)propanoic acid) hydrochloride.

[0638] MS (ESI) M / Z: 780.5 [(M+H] + .

[0639] 1 H NMR(400MHz,D2O)δ7.47-7.34(m,5H),7.32-7.18(m,7H),4.58-4.50(s,1H), 4.38-4.16(m,3H),3.67-3.61(m,3H),3.49-3.44(m,3H),3.37-3.26(m,4H), 3.15-3.08(m,3H),3.02-2.75(m,9H),2.70-2.56(m,4H),2.46-2.30(m,1H), 2.26-2.18(m,4H),2.10-1.93(m,4H),1.85-1.73(m,4H),1.58-1.49(m,1H).

[0640] Example 148-2

[0641] (2S,2'S)-3,3'-((1S,3S)-3-(3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)phenoxy)cyclobutyl)azinediyl)bis(methylene))bis(3,1-phenylene))bis(2-(((R)-pyrrolidin-3-yl)propanoic acid)

[0642] It can also be prepared according to the following steps:

[0643] Reaction route:

[0644] Steps:

[0645] Step A: At room temperature, tert-butyl (R)-3-((S)-3-(3-bromophenyl)-1(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (1.8 g, 3.96 mmol) and boric acid (367 mg, 5.94 mmol) were dissolved in 1-methyl-2-pyrrolidone (15 mL) under nitrogen. Cesium carbonate (2.6 g, 7.92 mmol), palladium acetate (178 mg, 0.79 mmol), and 2-(di-tert-butylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-1-propyl-1,1'-biphenyl (766 mg, 1.58 mmol) were then added to the solution. The reaction was stirred at 80°C for 16 hours.

[0646] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was slowly added to water (100 mL). The mixture was extracted with ethyl acetate (100 mL × 3 times), and the organic phases were combined and washed with saturated brine (50 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column to obtain 930 mg of tert-butyl (R)-3-(S)-1-(tert-butoxy)-3-(3-hydroxyphenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate.

[0647] MS (ESI) M / Z: 392.3 [M+H] + .

[0648] Step B: At room temperature under nitrogen, dissolve tert-butyl (R)-3-(S)-1-(tert-butoxy)-3-(3-hydroxyphenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (500 mg, 1.28 mmol) in 1,4-dioxane (10 mL). Subsequently, benzyl ((1S,3S)-3-hydroxycyclobutyl)carbamate (340 mg, 1.54 mmol) and cyanomethylenetri-n-butylphosphine (371 mg, 1.54 mmol) were added to the solution. The reaction system was stirred at 100°C for 8 hours.

[0649] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 630 mg of tert-butyl (R)-3-((S)-3-(3)-(1R,3S)-3-(benzyloxy)carbonyl)amino)cyclobutyloxy)phenyl)-1-(tert-butoxy-1-oxopropan-2-yl)pyrrolidine-1-carboxylate.

[0650] MS (ESI) M / Z: 595.3 [M-99] + .

[0651] Step C: Dissolve tert-butyl (R)-3-((S)-3-(3)-(1R,3S)-3-(benzyloxy)carbonyl)amino)cyclobutyloxy)phenyl)-1-(tert-butoxy-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (630 mg, 1.06 mmol) in methanol (8 mL) at room temperature. Then, add 10 wt% palladium on carbon (60 mg). The hydrogen atmosphere is replaced by vacuum evacuation three times, and the reaction system is stirred at room temperature for 16 hours.

[0652] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was filtered and concentrated under reduced pressure to obtain 340 mg of tert-butyl (R)-3-(S)-3-(3-(1R,3S)-3-aminocyclobutyloxy)phenyl)-1-(tert-butoxy-1-oxopropan-2-yl)pyrrolidine-1-carboxylate.

[0653] MS (ESI) M / Z: 461.3 [M+H] + .

[0654] Step D: Tert-butyl (R)-3-(S)-3-(1R,3S)-3-aminocyclobutyloxy)phenyl)-1-(tert-butoxy-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (230 mg, 0.5 mmol), tert-butyl (R)-3-((S)-3-(3-(bromomethyl)phenyl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (490 mg, 1.05 mmol), potassium carbonate (138 mg, 1.0 mmol), and potassium iodide (166 mg, 1.0 mmol) were dissolved in acetonitrile (15 mL) at room temperature under nitrogen. The reaction was then stirred at 45°C for 16 hours.

[0655] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was slowly added to an aqueous solution (50 mL) to quench the reaction. The mixture was extracted with ethyl acetate (50 mL x 3), and the organic phases were combined and washed with saturated brine (30 mL x 2). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by reverse-phase column chromatography to yield 110 mg of 3,3'-((2S,2'S)-(1S,3S)-3-(3-(S)-3-(tert-butyloxy)-2-((R)-1-(tert-butyloxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenoxy)cyclobutyl)azepanadiyl)bis(methylene))bis(3,1-phenylene)bis(3-(tert-butyloxy)-3-oxopropane-1,2-diyl))(3R,3'R)bis(pyrrolidine-1-carboxylate).

[0656] MS (ESI) M / Z: 1235.6 [M+H] + .

[0657] Step E: 3,3'-((2S,2'S)-(1S,3S)-3-(3-(S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenoxy)cyclobutyl)azepinediyl)bis(methylene))bis(3,1-phenylene)bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)bis(pyrrolidine-1-carboxylate) (40 mg, 0.03 mmol) was dissolved in dry dichloromethane (1.5 mL) at room temperature. 4M hydrochloric acid-1,4-dioxane (3.0 mL) was then slowly added dropwise to the solution. The reaction was stirred for 16 hours.

[0658] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was filtered and the filter cake was rinsed with dichloromethane (10 mL x 2). The resulting filter cake was purified by preparative HPLC (0.1% aqueous HCl / acetonitrile) and lyophilized to obtain 13 mg of (2S,2'S)-3,3'-((1S,3S)-3-(3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)phenoxy)cyclobutyl)azinediyl)bis(methylene))bis(3,1-phenylene))bis(2-(((R)-pyrrolidin-3-yl)propanoic acid) hydrochloride.

[0659] MS (ESI) M / Z: 384.2 [M / 2+H] + .

[0660] 1 H NMR(400MHz,D2O)δ7.38-7.34(m,2H),7.31-7.29(m,2H),7.26-7.19(m,3H) ,7.17(s,2H),6.94(d,J=7.6Hz,1H),6.68-6.61(m,2H),4.29-4.08(m,5H),3 .61-3.50(m,3H),3.43-3.31(m,3H),3.27-3.15(m,3H),3.07-2.96(m,3H),2 .95-2.45(m,15H),2.42-2.23(m,2H),2.18-2.05(m,3H),1.78-1.62(m,3H).

[0661] Example 148-1

[0662] (2S,2'S)-3,3'-((1R,3S)-3-(3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)phenoxy)cyclobutyl)azinediyl)bis(methylene))bis(3,1-phenylene))bis(2-(((R)-pyrrolidin-3-yl)propanoic acid)

[0663] The synthesis of Example 148-1 refers to Example 148-2.

[0664] MS (ESI) M / Z: 384.2 [M / 2+H] + .

[0665] 1 H NMR (400MHz, D2O) δ7.54-7.41(m,4H),7.37(d,J=7.2Hz,2H),7.32(s,2H),7.24(d,J=8.4Hz,2H),8.88(d,J=8.4Hz,2H),4.60-4.50(m,1H),4.43-4 .23(s,4H),3.82-3.62(m,3H),3.57-3.47(m,3H),3.40-3.29(m,3H),3.2 3-3.75(m,15H),2.73-2.56(m,3H),2.41-2.20(m,5H),1.92-1.77(m,3H).

[0666] Example 154

[0667] (2S,2'S)-3,3'-((2-((3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)benzyl)amino)propane-1,3-diyl)bis(3,1-phenylene))bis(2-(R)pyrrolidin-3-yl)propanoic acid)

[0668] It can also be prepared according to the following steps:

[0669] Reaction route:

[0670] Steps:

[0671] Step A: In an ice-water bath under nitrogen, dissolve dimethyl malonate (103 mg, 0.78 mmol) in N,N-dimethylformamide (4 mL). Add 60 wt% sodium hydride (69 mg, 1.71 mmol) to the solution and stir for 30 minutes. Then, add tert-butyl (R)-3-((S)-3-(3-(bromomethyl)phenyl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (800 mg, 1.71 mmol), warm to 50°C, and stir for 5 hours.

[0672] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched by adding water (30 mL). The mixture was extracted with ethyl acetate (20 mL × 3 times), and the organic phases were combined and washed with saturated brine (30 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 550 mg of dimethyl 2,2-bis(3-(((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)benzyl)malonate.

[0673] MS (ESI) M / Z: 929.5 [M+23] + .

[0674] Step B: Dimethyl 2,2-bis(3-(((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)benzyl)malonate (550 mg, 0.61 mmol) was dissolved in n-butanol / water (3 mL, v / v, 1:1) at room temperature. Sodium hydroxide (243 mg, 6.1 mmol) was then added to the solution. The reaction was stirred at 80°C for 4 hours.

[0675] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched with water (20 mL) and the pH was adjusted to 4 with 1 M dilute hydrochloric acid. The mixture was extracted with ethyl acetate (30 mL × 3 times), and the organic phases were combined and washed with saturated brine (20 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 400 mg of 2-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)benzyl)-3-(3-(S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)propanoic acid.

[0676] Step C: 2-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)benzyl)-3-(3-(S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)propanoic acid (400 mg, 0.48 mmol) was dissolved in toluene (2.4 mL) at room temperature under nitrogen. Diphenylphosphoryl azide (264 mg, 0.96 mmol), triethylamine (242 mg, 2.4 mmol), and benzyl alcohol (260 mg, 2.4 mmol) were then added dropwise to the solution. The reaction system was stirred at 100°C for 2 hours.

[0677] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched by adding water (20 mL). The mixture was extracted with ethyl acetate (30 mL x 3 times), and the organic phases were combined and washed with saturated brine (20 mL x 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 400 mg of 3,3'-di-tert-butyl((2S,2'S)-((2-((benzyloxy)carbonyl)amino)propane-1,3-diyl)bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate).

[0678] MS (ESI) M / Z: 962.4 [M+23] + .

[0679] Step D: 3,3'-di-tert-butyl((2S,2'S)-((2-((benzyloxy)carbonyl)amino)propane-1,3-diyl)bis(3,1-phenylene))bis(3-(tert-butyloxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate) (400 mg, 0.43 mmol) was dissolved in isopropanol (2.2 mL) at room temperature. 10 wt% palladium on carbon (80 mg) was then added to the solution. The hydrogen atmosphere was replaced by air under vacuum three times, and the reaction system was stirred at room temperature for 16 hours.

[0680] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was filtered, and the filtrate was collected and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 350 mg of 3,3'-di-tert-butyl((2S,2'S)-((2-aminopropane-1,3-diyl)bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate).

[0681] MS (ESI) M / Z: 806.4 [M+H] + .

[0682] Step E: 3,3'-di-tert-butyl((2S,2'S)-((2-aminopropane-1,3-diyl)bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate) (100 mg, 0.12 mmol), (R)-tert-butyl 3-((S)-3-(3-(bromomethyl)phenyl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (53 mg, 0.11 mmol), potassium carbonate (30 mg, 0.22 mmol), and potassium iodide (37 mg, 0.22 mmol) were dissolved in acetonitrile (3.7 mL) at room temperature. The reaction was stirred at 40°C for 5 hours.

[0683] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched by adding water (25 mL). The mixture was extracted with ethyl acetate (20 mL x 3), and the organic phases were combined and washed with saturated brine (30 mL x 2). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 100 mg of 3,3'-di-tert-butyl((2S,2'S)-(2-(((3-((S)-3-(tert-butyloxy)-2-((R)-1-(tert-butyloxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)benzyl)amino)propane-1,3-diyl)bis(3,1-phenylene))bis(3-(tert-butyloxy)-3-oxypropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate).

[0684] MS (ESI) M / Z: 547.4 [(M-100) / 2+H] + .

[0685] Step F: 3,3'-di-tert-butyl((2S,2'S)-(2-(((3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)benzyl)amino)propane-1,3-diyl)bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxypropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate) (50 mg, 0.04 mmol) was dissolved in dry dichloromethane (2.0 mL) at room temperature. 4M hydrochloric acid-dioxane (4.0 mL) was then added dropwise to the solution. The reaction was stirred at room temperature for 16 hours.

[0686] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was filtered and the filter cake was rinsed with dichloromethane (5 mL x 2). The resulting filter cake was purified by preparative HPLC (0.1% aqueous HCl / acetonitrile) and lyophilized to obtain 6.76 mg of (2S,2'S)-3,3'-((2-((3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)benzyl)amino)propane-1,3-diyl)bis(3,1-phenylene))bis(2-(R)pyrrolidin-3-yl)propanoic acid) hydrochloride.

[0687] MS (ESI) M / Z: 363.3 [(M / 2+H] + .

[0688] 1 H NMR(400MHz,D2O)δ7.27-7.11(m,4H),7.05-7.03(m,2H),6.98-6.78(m,6H),4.01(s,2H),3.57-3.43(m,4H),3.34-3.28(m ,3H),3.20-3.07(m,3H),3.02-2.67(m,13H),2.63-2.51(m,3H),2.50-2.35(m,3H),2.27-1.96(m,3H),1.72-1.55(m,3H).

[0689] Example 179

[0690] (2S,2'S,2'S)-3,3',3'-((2,4,6-trioxo-1,3,5-triazine-1,3,5-trimethyl)tris(methylene))tris(phenyl-3,1-diyl))tris(2-(((R)-pyrrolidin-3-yl)propanoic acid)

[0691] It can also be prepared according to the following steps:

[0692] Reaction route:

[0693] Steps:

[0694] Step A: Dissolve 1,3,5-triazine-2,4,6-trione (64 mg, 0.50 mmol) in dry tetrahydrofuran (3.0 mL) at 0°C under nitrogen. Then, add triphenylphosphine (520 mg, 1.98 mmol) and diisopropyl azodicarboxylate (400 mg, 1.98 mmol) sequentially to the solution. Warm the mixture to room temperature and stir for 5 minutes. Then, cool the mixture to 0°C and slowly add a solution of tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(3-(hydroxymethyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (650 mg, 1.60 mmol) in tetrahydrofuran (2.0 mL). Warm the mixture to room temperature and continue stirring for 4 hours.

[0695] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched by adding ice water (50 mL). The mixture was extracted with ethyl acetate (30 mL x 3), and the organic phases were combined and washed with saturated brine (30 mL x 2). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 271 mg of 3,3',3'-((2S,2'S,2'S)-((2,4,6-trioxo-1,3,5-triazine-1-,3,5-triyl)tris(methylene))tris(benzene-3,1-diyl)tris(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R,3'R)-tris(pyrrolidine-1-carboxylate).

[0696] Step B: 3,3',3'-((2S,2'S,2'S)-((2,4,6-trioxo-1,3,5-triazine-1-,3,5-triyl)tris(methylene))tris(benzene-3,1-diyl)tris(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R,3'R)-tris(pyrrolidine-1-carboxylate) (270 mg, 0.21 mmol) was dissolved in dry dichloromethane (2.0 mL) at 0°C under nitrogen. 4M hydrochloric acid-dioxane (4.0 mL) was then added dropwise to the solution. The reaction was stirred at room temperature for 16 hours.

[0697] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was filtered, the filter cake was rinsed with dichloromethane (10 mL × 2 times), the solid was collected, and dried in vacuo to obtain 147.10 mg of (2S,2'S,2'S)-3,3',3'-((2,4,6-trioxo-1,3,5-triazine-1,3,5-trimethyl)tris(methylene))tris(benzene-3,1-diyl))tris(2-(((R)-pyrrolidin-3-yl)propanoic acid) hydrochloride.

[0698] MS (ESI) M / Z: 823.4 [M+H]+ .

[0699] 1 H NMR(400MHz,D2O)δ7.25-7.16(m,3H),7.12-7.02(m,9H),4.90(s,6H),3.49-3.39(m,3H),3.38-3.29(m,3H),3.21-3.10( m,3H),2.99-2.88(m,3H),2.82-2.69(m,6H),2.68-2.58(m,3H),2.50-2.37(m,3H),2.13-2.01(m,3H),1.72-1.59(m,3H).

[0700] Example 228-1

[0701] (2S,2'S)-3,3'-((1R,3R)-3-(4-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)phenoxy)cyclobutyl)nitrogendiyl)bis(methylene))bis(3,1-phenylene))bis(2-(((R)-pyrrolidin-3-yl)propanoic acid)

[0702] The synthesis of Example 228-1 refers to Example 148-2.

[0703] MS (ESI) M / Z: 384.2 [M / 2+H] + .

[0704] 1 H NMR(400MHz,D2O)δ7.41-7.27(m,4H),7.26-7.24(m,5H),6.84(d,J=7.2Hz,1H),6.72-6.62(m,2H),4.48-4.38(m,1H),4.32-4.10(m,4H) ,3.69-3.48(m,4H),3.45-3.33(m,3H),3.28-3.15(m,3H),3.11-3.26(m,14H),2.61-2.44(m,3H),2.33-2.06(m,5H),1.78-1.64(m,3H).

[0705] Example 228-2

[0706] (2S,2'S)-3,3'-((1S,3S)-3-(4-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)phenoxy)cyclobutyl)azinediyl)bis(methylene))bis(3,1-phenylene))bis(2-(((R)-pyrrolidin-3-yl)propanoic acid)

[0707] The synthesis of Example 228-2 was based on Example 148-2.

[0708] MS (ESI) M / Z: 384.2 [M / 2+H] + .

[0709] 1 H NMR(400MHz,D2O)δ7.41-7.26(m,4H),7.25-7.08(m,6H),6.76-6.67(m,2H),4.31-4.09(m,5H),3.61-3.49(m,3H),3.42-3.3 2(m,3H),3.27-3.15(m,3H),3.08-2.95(m,3H),2.94-2.43(m,15H),2.42-2.24(m,2H),2.19-2.04(m,3H),1.79-1.61(m,3H).

[0710] Example 123

[0711] (2S,2'S)-3,3'-((5-((S)-2-carboxy-2-((R))-pyrrolidin-3-yl)ethyl)-2-oxo-1H-benzo[d]imidazole-1,3(2H)-diyl)bis(3,1-phenylene))bis(2-(((R)-pyrrolidin-3-yl)propanoic acid

[0712] It can also be prepared according to the following steps:

[0713] Reaction route:

[0714] Steps:

[0715] Step A: At -30°C under nitrogen, slowly add 1 M lithium bistrimethylsilylamide (1.6 mL, 0.16 mmol) dropwise to a solution of (R)-tert-butyl 3-(2-((S)-4-benzyl-2-oxooxazolidin-3-yl)-2-oxoethyl)pyrrolidine-1-carboxylate (500 mg, 1.29 mmol) in tetrahydrofuran (30 mL) and stir for 0.5 hour. Subsequently, slowly add a solution of 1-bromo-4-(bromomethyl)-2-nitrobenzene (498 mg, 1.7 mmol) in tetrahydrofuran (5 mL) and stir for 1 hour. The reaction system is then warmed to 0°C and stirred for 2 hours.

[0716] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was slowly added to an ice-cold saturated ammonium chloride solution (200 mL) to quench. The mixed solution was extracted with ethyl acetate (100 mL × 3 times), and the organic phases were combined and washed with saturated brine (200 mL × 2 times). It was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column to obtain 500 mg of tert-butyl (R)-3-((S)-1-((S)-4-benzyl-2-oxooxazolidin-3-yl)-3-(4-bromo-3-nitrophenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate.

[0717] MS (ESI) M / Z: 546.1 [M-55] + .

[0718] Step B: Tert-butyl (R)-3-((S)-1-((S)-4-benzyl-2-oxooxazolidin-3-yl)-3-(4-bromo-3-nitrophenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (200 mg, 0.34 mmol) was dissolved in tetrahydrofuran (5 mL) at 0°C. A 33 wt% aqueous solution of hydrogen peroxide (0.6 mL, 0.51 mmol) and an aqueous solution of lithium hydroxide monohydrate (21.4 mg, 0.51 mmol) (0.6 mL) were then slowly added dropwise to the solution. The reaction system was then stirred for 3 hours.

[0719] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was slowly quenched with a saturated aqueous solution of sodium bisulfite (12 mL) at 0°C and the pH was adjusted to >12 with a saturated aqueous sodium hydroxide solution. The mixture was extracted with methyl tert-butyl ether (20 mL × 4 times), and the resulting aqueous phase was adjusted to pH 3 with 8M hydrochloric acid. The aqueous phase was then extracted with ethyl acetate (20 mL × 3 times), and the organic phases were combined and washed with saturated brine (20 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. 130 mg of (2S)-3-(4-bromo-3-nitrophenyl)-2-[(3R)-1-[(tert-butoxy)carbonyl]pyrrolidin-3-yl]propanoic acid was obtained.

[0720] MS (ESI) M / Z: 343.0 [M-99] + .

[0721] Step C: (2S)-3-(4-bromo-3-nitrophenyl)-2-[(3R)-1-[(tert-butoxy)carbonyl]pyrrolidin-3-yl]propanoic acid (130 mg, 0.29 mmol) was dissolved in 2-methyltetrahydrofuran (5 mL) at room temperature under nitrogen. O-tert-butyl-N,N'-diisopropylisourea (500 mg, 2.5 mmol) was then added to the solution, and the reaction system was heated to 65°C and stirred for 16 h.

[0722] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was filtered through celite and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 100 mg of tert-butyl (3R)-3-[(2S)-3-(4-bromo-3-nitrophenyl)-1-(tert-butoxy)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate.

[0723] Step D: At room temperature, under nitrogen protection, tert-butyl (3R)-3-[(2S)-3-(4-bromo-3-nitrophenyl)-1-(tert-butoxy)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (100 mg, 0.20 mmol), tert-butyl (3R)-3-[(2S)-3-(3-aminophenyl)-1-(tert-butoxy)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (78.1 mg, 0.20 mmol) and tert-butyl (3R)-3-[(2S)-3-(3-aminophenyl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (78.1 mg, 0.20 mmol) were added. g, 0.20 mmol), dicyclohexyl[3,6-dimethoxy-2',4',6'-triisopropyl[1,1'-biphenyl]-2-yl]phosphine (32.2 mg, 0.06 mmol), palladium acetate (13.5 mg, 0.06 mmol), and sodium tert-butoxide (38.44 mg, 0.40 mmol) were dissolved in 1,4-dioxane (6 mL), and the reaction system was stirred at 110 ° C for 16 h.

[0724] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was slowly added to a saturated ammonium chloride solution (20 mL) to quench the mixture. The mixture was extracted with ethyl acetate (20 mL × 3 times), and the organic phases were combined and washed with saturated brine (40 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 60 mg of tert-butyl (3S)-3-[(2R)-3-(tert-butoxy)-1-(4-[(3-[(2R)-3-(tert-butoxy)-2-[(3S)-1-[(tert-butoxy)carbonyl]pyrrolidin-3-yl]-3-oxopropyl]phenyl)amino]-3-nitrophenyl)-1,1-dihydro-3-oxopropan-2-yl]pyrrolidine-1-carboxylate.

[0725] Step E: Tert-butyl (3S)-3-[(2R)-3-(tert-butoxy)-1-(4-[(3-[(2R)-3-(tert-butoxy)-2-[(3S)-1-[(tert-butoxy)carbonyl]pyrrolidin-3-yl]-3-oxopropyl]phenyl)amino]-3-nitrophenyl)-1,1-dihydro-3-oxopropan-2-yl]pyrrolidine-1-carboxylate (60 mg) was dissolved in methanol (5 mL) under nitrogen at room temperature. 10 wt% palladium on carbon (20 mg) was then added to the solution, and the hydrogen atmosphere was replaced by air under vacuum three times. The reaction system was stirred at room temperature for 16 hours.

[0726] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was filtered through celite and concentrated under reduced pressure to obtain 50 mg of tert-butyl (3S)-3-[(2R)-3-(3-amino-4-[(3-[(2R)-3-(tert-butoxy)-2-[(3S)-1-[(tert-butoxy)carbonyl]pyrrolidin-3-yl]-3-oxopropyl]phenyl)amino]phenyl)-1-(tert-butoxy)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate.

[0727] MS (ESI) M / Z: 679.4 [M-99] + .

[0728] Step F: Tert-butyl (3S)-3-[(2R)-3-(3-amino-4-[(3-[(2R)-3-(tert-butoxy)-2-[(3S)-1-[(tert-butoxy)carbonyl]pyrrolidin-3-yl]-3-oxopropyl]phenyl)amino]phenyl)-1-(tert-butoxy)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (50 mg, 0.065 mmol) was dissolved in tetrahydrofuran (3 mL) at room temperature under nitrogen. N,N'-carbonyldiimidazole (31.62 mg, 0.21 mmol) was then added to the solution, and the reaction system was heated to 40°C and stirred for 16 h.

[0729] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched by adding water (10 mL). The mixture was extracted with ethyl acetate (5 mL × 3 times), and the organic phases were combined and washed with saturated sodium chloride aqueous solution (5 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 50 mg of (3S)-3-[(2R)-1-(tert-butoxy)-3-(1-(3-[(2R)-3-(tert-butoxy)-2-[(3S)-1-[(tert-butoxy)carbonyl]pyrrolidin-3-yl]-3-oxopropyl]phenyl)-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-5-yl)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate.

[0730] MS (ESI) M / Z: 705.4 [M-99] + .

[0731] Step G: At room temperature, under nitrogen protection, tert-butyl (3S)-3-[(2R)-1-(tert-butoxy)-3-(1-(3-[(2R)-3-(tert-butoxy)-2-[(3S)-1-[(tert-butoxy)carbonyl]pyrrolidin-3-yl]-3-oxopropyl]phenyl)-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-5-yl)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (50 mg, 0.062 mmol), ... R)-3-[(2S)-3-(3-bromophenyl)-1-(tert-butoxy)-1-oxopropyl-2-yl]pyrrolidine-1-carboxylate (28.17 mg, 0.062 mmol), potassium carbonate (29.99 mg, 0.22 mmol), cuprous iodide (17.71 mg, 0.093 mmol) and N,N'-dimethylethylenediamine (16.74 mg, 0.19 mmol) were dissolved in toluene (5 mL), and then the reaction system was heated to 100 ° C and stirred for 16 h.

[0732] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched with water (10 mL). The mixture was extracted with ethyl acetate (5 mL × 3 times), and the organic phases were combined and washed with saturated sodium chloride (5 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 40 mg of di-tert-butyl 3,3'-((2S,2'S)-((5-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)-2-oxo-1H-benzo[d]imidazole-1,3(2H)-diyl)bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropyl-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate).

[0733] Step H: At room temperature, under nitrogen protection, di-tert-butyl 3,3'-((2S,2'S)-((5-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)-2-oxo-1H-benzo[d]imidazole-1,3(2H)-diyl)bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropyl-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate) (40 mg, 0.034 mmol) was dissolved in dichloromethane (2 mL). Subsequently, trifluoroacetic acid (2 mL) was added to the above solution, and the reaction system was heated to 100°C and stirred for 16 h.

[0734] LCMS monitoring showed the disappearance of the starting material. The reaction mixture was filtered, and the filter cake was rinsed with dichloromethane (5 mL x 2). The resulting filter cake was purified by preparative HPLC (0.1% aqueous HCl / acetonitrile) and lyophilized to obtain 25.75 mg of (2S,2'S)-3,3'-((5-((S)-2-carboxy-2-((R))-pyrrolidin-3-yl)ethyl)-2-oxo-1H-benzo[d]imidazole-1,3(2H)-diyl)bis(3,1-phenylene))bis(2-(((R)-pyrrolidin-3-yl)propanoic acid trifluoroacetate).

[0735] MS (ESI) M / Z: 710.4 [M+H] + .

[0736] 1 H NMR(400MHz,D2O)δ7.59-7.45(m,2H),7.44-7.24(m,6H),6.98(s,2H),6.86(s,1H),3.61-3.43(m,3H),3.4 4-3.30(m,3H),3.28-3.16(m,3H),3.06-2.64(m,12H),2.60-2.41(m,3H),2.14(s,3H),1.81-1.64(m,3H).

[0737] Example 124

[0738] (2S,2'S)-3,3'-((2-oxo-5-(piperazin-1-yl)-1H-benzo[d]imidazole-1,3(2H)-diyl)bis(3,1-phenylene))bis(2-((R)-pyrrolidin-3-yl)propanoic acid)

[0739] It can also be prepared according to the following steps:

[0740] Reaction route:

[0741] Steps:

[0742] Step A: At room temperature, under nitrogen protection, 4-fluoro-1,2-dinitrobenzene (100 mg, 0.54 mmol), tert-butyl piperazine-1-carboxylate (121 mg, 0.65 mmol) and potassium carbonate (220 mg, 1.62 mmol) were dissolved in DMF (3 mL), and then the reaction system was heated to 40 ° C and stirred for 16 h.

[0743] After LCMS monitoring showed the disappearance of the starting material, water (10 mL) was added to the system to quench the reaction. The mixture was extracted with ethyl acetate (10 mL × 3 times). The organic phases were combined and washed with saturated aqueous sodium chloride (10 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 120 mg of tert-butyl 4-(3,4-dinitrophenyl)piperazine-1-carboxylate.

[0744] MS (ESI) M / Z: 253.1 [M-99] +

[0745] Step B: Dissolve tert-butyl 4-(3,4-dinitrophenyl)piperazine-1-carboxylate (120 mg, 0.34 mmol) in methanol (5 mL) at room temperature. Add 10 wt% palladium on carbon (80 mg). Vacuum the solution three times to replace the hydrogen atmosphere. Stir the reaction system at room temperature for 16 hours.

[0746] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was filtered, the filtrate was collected, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 100 mg of tert-butyl 4-(3,4-diaminophenyl)piperazine-1-carboxylate.

[0747] MS (ESI) M / Z: 293.2 [M+H] +

[0748] Step C: Dissolve tert-butyl 4-(3,4-diaminophenyl)piperazine-1-carboxylate (100 mg, 0.34 mmol) in tetrahydrofuran (5 mL) at room temperature under nitrogen. Add N,N'-carbonyldiimidazole (165.39 mg, 1.02 mmol) to the solution, and heat the reaction system to 40°C and stir for 16 h.

[0749] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched with water (10 mL). The mixture was extracted with ethyl acetate (10 mL × 3 times), and the organic phases were combined and washed with saturated aqueous sodium chloride (10 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 100 mg of tert-butyl 4-(2-oxo-2,3-dihydro-1H-1,3-benzodiazol-5-yl)piperazine-1-carboxylate.

[0750] MS (ESI) M / Z: 319.1 [M+H] + .

[0751] Step D: At room temperature, under nitrogen protection, tert-butyl 4-(2-oxo-2,3-dihydro-1H-1,3-benzodiazol-5-yl)piperazine-1-carboxylate (100 mg, 0.31 mmol), (3R)-3-[(2S)-3-(3-bromophenyl)-1-(tert-butoxy)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (312.67 mg, 0.69 mmol), potassium carbonate (101 mg, 0.77 mmol), cuprous iodide (63.26 mg, 0.33 mmol)) and N,N'-dimethylethylenediamine (58.15 mg, 0.66 mmol) were dissolved in toluene (5 mL), and then the reaction system was heated to 100 ° C and stirred for 16 h.

[0752] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched by adding water (10 mL). The mixture was extracted with ethyl acetate (10 mL × 3 times), and the organic phases were combined and washed with saturated sodium chloride aqueous solution (10 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 80 mg of tert-butyl 4-(1,3-bis(3-[(2S)-3-(tert-butoxy)-2-[(3R)-1-[(tert-butoxy)carbonyl]pyrrolidin-3-yl]-3-oxopropyl]phenyl)-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-5-yl)piperazine-1-carboxylate.

[0753] Step E: Tert-butyl 4-(1,3-bis(3-[(2S)-3-(tert-butoxy)-2-[(3R)-1-[(tert-butoxy)carbonyl]pyrrolidin-3-yl]-3-oxopropyl]phenyl)-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-5-yl)piperazine-1-carboxyl (80 mg, 0.075 mmol) was dissolved in hydrochloric acid-dioxane (3 mL), and the reaction system was heated to 60° C. and stirred for 16 h.

[0754] LCMS monitoring showed the disappearance of the starting material. The reaction mixture was filtered, and the filter cake was rinsed with dichloromethane (5 mL x 2). The resulting filter cake was purified by preparative HPLC (0.1% aqueous HCl / acetonitrile) and lyophilized to obtain 21.2 mg of (2S,2'S)-3,3'-((2-oxo-5-(piperazin-1-yl)-1H-benzo[d]imidazole-1,3(2H)-diyl)bis(3,1-phenylene))bis(2-((R)-pyrrolidin-3-yl)propanoic acid) hydrochloride.

[0755] MS (ESI) M / Z: 653.4 [M+H] + .

[0756] 1H NMR(400MHz,D2O)δ7.61-7.47(m,2H),7.43-7.32(m,6H),7.03(d,J=8.8Hz,1H),6.91( dd,J=8.8Hz,2.0Hz,1H),6.74(d,J=2.0Hz,1H),3.64-3.52(m,2H),3.42-3.36(m,2H), 3.36-3.26(m,8H),3.25-3.18(m,2H),3.09-3.02(m,2H),3.01-2.96(m,2H),2.95-2.8 6(m,2H),2.82-2.75(m,2H),2.61-2.48(m,2H),2.22-2.08(m,2H),1.82-1.66(m,2H).

[0757] Example 12

[0758] (2S,2'S)-3,3'-(7-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)-2,3-dihydrobenzo[b][1,4]dioxol-5-yl)methyl)azepinediyl)bis(methylene))bis(3,1-phenylene))bis(2-((R)-pyrrolidin-3-yl)propanoic acid)

[0759] It can also be prepared according to the following steps:

[0760] Reaction route:

[0761] Steps:

[0762] Step A: At room temperature under nitrogen protection, 3,3'-((2S,2'S)-((azadiylbis(methylene))bis(3,1-phenylene))-bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate) (90 mg, 0.11 mmol), (R)-tert-butyl 3-((S)-3-(8-(bromomethyl)-2,3-dihydrobenzo[b][1,4]dioxan-6-yl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (60 mg, 0.11 mmol), potassium carbonate (31 mg, 0.23 mmol) and potassium iodide (38 mg, 0.23 mmol) were dissolved in acetonitrile (10 mL). The reaction system was then stirred at 40°C for 4 hours.

[0763] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched by adding water (80 mL). The mixture was extracted with ethyl acetate (30 mL x 3), and the organic phases were combined and washed with saturated brine (30 mL x 2). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 65 mg of 3,3'-di-tert-butyl((2S,2'S)-(7-(((S)-3-(tert-butyloxy)-2-((R)-1-(tert-butyloxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)-2,3-dihydrobenzo[b][1,4]dioxolan-5-yl)methyl)azinediyl)bis(methylene))bis(3,1-phenylene)bis(3-(tert-butyloxy)-3-oxypropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate).

[0764] MS (ESI) M / Z: 569.5 [(M-100 / 2) + H] + .

[0765] Step B: At room temperature, under nitrogen protection, 3,3'-di-tert-butyl((2S,2'S)-(7-(((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)-2,3-dihydrobenzo[b][1,4]dioxolan-5-yl)methyl)azinediyl)bis(methylene))bis(3,1-phenylene)bis(3-(tert-butoxy)-3-oxypropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate) (65 mg, 0.05 mmol) was dissolved in dry dichloromethane (1 mL). Subsequently, 4M hydrochloric acid-1,4-dioxane solution (4 mL) was added dropwise to the above solution. The reaction system was then stirred at 40 degrees Celsius for 16 hours.

[0766] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was filtered, and the filter cake was rinsed with dichloromethane (10 mL×2 times). The filter cake was collected and lyophilized to obtain 38 mg of (2S,2'S)-3,3'-(7-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)-2,3-dihydrobenzo[b][1,4]dioxol-5-yl)methyl)azepinediyl)bis(methylene))bis(3,1-phenylene))bis(2-((R)-pyrrolidin-3-yl)propionic acid) hydrochloride.

[0767] MS (ESI) M / Z: 385.3 [M / 2+H] +

[0768] 1H NMR(400MHz,D2O)δ7.34(t,J=7.6Hz,2H),7.29(d,J=7.6Hz,2H),7.15(d,J=7.6 Hz,2H),7.09(s,2H),6.77(s,1H),6.56(s,1H),4.46-4.12(m,6H),4.11-3.97(m ,4H),3.61-3.49(m,3H),3.42-3.31(m,3H),3.26-3.13(m,3H),3.07-2.94(m,3 H),2.92-2.57(m,9H),2.55-2.41(m,3H),2.18-2.03(m,3H),1.77-1.61(m,3H).

[0769] Example 273

[0770] (S)-3-(3-(((7-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)-2,3-dihydro-1H-inden-5-yl)methyl)1-(3-(S)2-carboxy-2-(R)pyrrolidin-3-ylethyl)phenyl)piperidin-4-yl)amino)methyl)phenyl)-2-(((R)-pyrrolidin-3-yl)propanoic acid)

[0771] The synthesis of Example 273 refers to Example 216.

[0772] MS (ESI) M / Z: 410.8 [M / 2+H] + .

[0773] 1 H NMR(400MHz,D2O)δ7.50-7.20(m,7H),7.17(s,1H),7.11(s,1H),6.97(s,1H),4.48-4.28(m,4H),3.83-3.51( m,6H),3.50-3.31(m,5H),3.28-3.15(m,3H),3.09-2.97(m,3H),2.96-2.72(m,10H),2.70-2.46(m,6H),2.45 -2.20(m,3H),2.19-2.07(m,3H),2.06-1.83(m,3H),1.78-1.62(m,3H).

[0774] Example 263

[0775] 2,2'-(3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)benzyl)nitrogendiyl)bis(methylene)bis(3,1-phenylene))bis(methyl)bis(4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine-3-carboxylic acid)

[0776] It can also be prepared according to the following steps:

[0777] Reaction route:

[0778] Steps:

[0779] Step A: 6-(tert-Butyl)-3-ethyl-1,4,5,7-tetrahydro-6-pyrazolo[3,4-c]pyridine-3,6-dicarboxylate (1.2 g, 4.3 mmol) and 3-(bromomethyl)benzaldehyde (1.0 g, 5.0 mmol) were dissolved in N,N-dimethylformamide (20 mL) at room temperature under nitrogen. Potassium carbonate (1.1 g, 8.0 mmol) was then added to the solution. The reaction was stirred for 5 hours.

[0780] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was added to ice water (50 mL) to quench the reaction. The mixture was extracted with ethyl acetate (50 mL × 3 times), and the organic phases were combined and washed with saturated brine (200 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 1.1 g of 6-(tert-butyl) 3-ethyl-2-(3-formylbenzyl)-2,4,5,7-tetrahydro-6-pyrazolo[3,4-c]pyridine-3,6-dicarboxylate.

[0781] MS (ESI) M / Z: 414.21 [M+H] + .

[0782] Step B: At 0°C under nitrogen, dissolve 6-(tert-butyl)-3-ethyl-2-(3-formylbenzyl)-2,4,5,7-tetrahydro-6-pyrazolo[3,4-c]pyridine-3,6-dicarboxylate (1.1 g, 2.7 mmol) in methanol (50 mL). Then, add sodium borohydride (0.3 g, 7.9 mmol). The reaction mixture is stirred for 0.5 hours.

[0783] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was filtered, the filtrate collected, and concentrated under reduced pressure. The resulting residue was diluted with water (200 mL), and the mixture was extracted with dichloromethane (100 mL x 2). The organic phases were combined and washed with saturated brine (200 mL x 2). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 1.1 g of 6-(tert-butyl)-3-ethyl-2-(3-(hydroxymethyl)benzyl)-2,4,5,7-tetrahydro-6-pyrazolo[3,4-c]pyridine-3,6-dicarboxylate.

[0784] MS (ESI) M / Z: 416.50 [M+H] + .

[0785] Step C: Dissolve 6-(tert-butyl)-3-ethyl-2-(3-(hydroxymethyl)benzyl)-2,4,5,7-tetrahydro-6-pyrazolo[3,4-c]pyridine-3,6-dicarboxylate (1.1 g, 2.7 mmol) in dichloromethane (50 mL) at 0°C under nitrogen. Carbon tetrabromide (1.8 g, 5.3 mmol) and triphenylphosphine (1.4 g, 5.3 mmol) were then added to the solution. The reaction was stirred at room temperature for 4 hours.

[0786] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was concentrated under reduced pressure, and ice water (50 mL) was added to the resulting residue to quench the reaction. The mixture was extracted with ethyl acetate (50 mL × 3 times), and the organic phases were combined and washed with saturated brine (50 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 0.78 g of 6-(tert-butyl)-3-ethyl-2-(3-(bromomethyl)benzyl)-2,4,5,7-tetrahydro-6-pyrazolo[3,4-c]pyridine-3,6-dicarboxylate.

[0787] MS (ESI) M / Z: 478.19 [M+H] + .

[0788] Step D: 6-(tert-Butyl)-3-ethyl-2-(3-(bromomethyl)benzyl)-2,4,5,7-tetrahydro-6-pyrazolo[3,4-c]pyridine-3,6-dicarboxylate (248 mg, 0.52 mmol) and (R)-tert-butyl 3-((S)-3-(3-(aminomethyl)phenyl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (100 mg, 0.25 mmol) were dissolved in acetonitrile (2 mL) under nitrogen at room temperature. Potassium carbonate (70 mg, 0.50 mmol) and potassium iodide (83 mg, 0.50 mmol) were then added to the solution. The reaction was stirred at 45°C for 4.5 hours.

[0789] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched by adding it to an ice-water mixture (20 mL). The mixture was extracted with ethyl acetate (20 mL x 3), and the organic phases were combined and washed with saturated brine (20 mL x 2). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 92 mg of 6-di-tert-butyl 3-diethyl 2,2'-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)benzyl)azinediyl)bis(methylene))bis(3,1-phenylene)bis(methyl)bis(methylene)(2,4,5,7-tetrahydro-6-pyrazolo[3,4-c]pyridine-3,6-dicarboxylate).

[0790] MS (ESI) M / Z: 1200.26 [M+H] + .

[0791] Step E: 6-di-tert-butyl 3-diethyl 2,2'-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)benzyl)azinediyl)bis(methylene))bis(3,1-phenylene)bis(methyl)bis(methylene)(2,4,5,7-tetrahydro-6-pyrazolo[3,4-c]pyridine-3,6-dicarboxylate) (100 mg, 0.08 mmol) was dissolved in methanol (1.0 mL) at room temperature. To this solution was added a solution of lithium hydroxide (10 mg, 0.4 mmol) in water (1 mL). The reaction was stirred for 18 hours.

[0792] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was filtered, the filter cake was rinsed with dichloromethane (2 mL×2 times), and concentrated under reduced pressure to obtain 38 mg of 2,2'-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)benzyl)nitrogendiyl)bis(methylene)bis(3,1-phenylene))bis(methyl)bis(6-(tert-butoxycarbonyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine-3-carboxylic acid).

[0793] MS (ESI) M / Z: 1143.98 [M+H] + .

[0794] Step F: 2,2'-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)benzyl)azinediyl)bis(methylene)bis(3,1-phenylene))bis(methyl)bis(6-(tert-butoxycarbonyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine-3-carboxylic acid) (38 mg, 0.03 mmol) was dissolved in 4M hydrochloric acid-1,4-dioxane solution (0.4 mL, 1.6 mmol) at room temperature under nitrogen. The reaction system was then stirred for 3 hours.

[0795] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was filtered, and the filter cake was rinsed with dichloromethane (2 mL×2 times). The filter cake was collected and lyophilized to obtain 17.69 mg of 2,2'-(3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)benzyl)nitrogendiyl)bis(methylene)bis(3,1-phenylene))bis(methyl)bis(4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine-3-carboxylic acid) hydrochloride.

[0796] MS (ESI) M / Z: 787.4 [M+H] + .

[0797] 1H NMR(400MHz,D2O)δ7.36-7.22(m,4H),7.20-7.10(m,4H),7.05-6.94(m,4H) ,5.58(s,4H),4.30-4.13(m,10H),3.62-3.50(m,1H),3.44-3.31(m,5H),3. 27-3.14(m,1H),3.07-2.93(m,5H),2.87-2.80(m,1H),2.78-2.69(m,1H),2 .68-2.59(m,1H),2.56-2.43(m,1H),2.17-2.05(m,1H),1.75-1.63(m,1H).

[0798] Example 269

[0799] (2S,2'S)-3,3'-(1R,4R)-4-(3-(((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)phenyl)cyclohexyl)nitrodiyl)bis(methylene)bis(3,1-phenylene))bis(2-(((R)-pyrrolidin-3-yl)propanoic acid)

[0800] The synthesis of Example 269 was carried out with reference to Example 134.

[0801] MS (ESI) M / Z: 779.5 [M+H] + .

[0802] 1 H NMR(400MHz,D2O)δ7.35-7.23(m,6H),7.19(s,1H),7.16-7.02(m,5H),4.26( d,J=13.2Hz,2H),4.09(d,J=13.6Hz,2H),3.62-3.50(m,3H),3.44-3.27(m,4H ),3.26-3.15(m,3H),3.08-2.96(m,4H),2.95-2.62(m,9H),2.58-2.45(m,3H) ,2.43-2.30(m,2H),2.18-2.05(m,3H),1.94-1.83(m,2H),1.80-1.54(m,7H).

[0803] Example 262

[0804] (2S,2'S)-3,3'-(1S,4S)-4-(3-(((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)phenyl)cyclohexyl)nitrodiyl)bis(methylene)bis(3,1-phenylene))bis(2-(((R)-pyrrolidin-3-yl)propanoic acid)

[0805] It can also be prepared according to the following steps:

[0806] Reaction route:

[0807] Steps:

[0808] Step A: At 0°C under nitrogen, dissolve methyl 4-iodobicyclo[2.2.2]octane-1-carboxylate (8 g, 27.20 mmol) in benzene (68 mL). Then, add aluminum chloride (13.4 g, 100.65 mmol). The reaction mixture is stirred at 60°C for 3 hours.

[0809] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was added to ice water (250 mL) to quench the reaction. The mixture was extracted with ethyl acetate (150 mL x 3 times), and the organic phases were combined and washed with saturated brine (200 mL x 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 6.23 g of methyl 4-phenylbicyclo[2.2.2]octane-1-carboxylate.

[0810] Step B: Methyl 4-phenylbicyclo[2.2.2]octane-1-carboxylate (6.23 g, 25.53 mmol) was dissolved in chloroform (142 mL) at 0°C under nitrogen. Silver trifluoroacetate (6.77 g, 30.64 mmol) and bromine (4.29 g, 26.81 mmol) were then added to the solution. The reaction was stirred at room temperature for 2 hours.

[0811] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was filtered and the filter cake was rinsed with ethyl acetate (70 mL x 4 times). All the filtrates were combined and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 7.24 g of methyl 4-(4-bromophenyl)bicyclo[2.2.2]octane-1-carboxylate.

[0812] Step C: Methyl 4-(4-bromophenyl)bicyclo[2.2.2]octane-1-carboxylate (7.24 g, 22.48 mmol) was dissolved in tetrahydrofuran (112 mL) at room temperature. Methanol (56 mL), water (28 mL), and lithium hydroxide monohydrate (3.78 g, 89.94 mmol) were then added to the solution. The reaction mixture was stirred for 2 hours.

[0813] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was added to ice water (100 mL) for quenching. The mixture was extracted with ethyl acetate (150 mL x 3 times), and the organic phases were combined and washed with saturated brine (200 mL x 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified on a silica gel column to yield 5.92 g of 4-(4-bromophenyl)bicyclo[2.2.2]octane-1-carboxylic acid.

[0814] Step D: At 0°C under nitrogen, 4-(4-bromophenyl)bicyclo[2.2.2]octane-1-carboxylic acid (5.92 g, 19.22 mmol) was dissolved in toluene (96 mL). Triethylamine (9.7 g, 96.10 mmol), diphenylphosphoryl azide (10.6 g, 38.49 mmol), and benzyl alcohol (10.2 g, 96.10 mmol) were then added to the solution. The reaction was stirred at 100°C for 3 hours.

[0815] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was slowly added to an ice-water solution (200 mL) to quench the mixture. The mixture was extracted with ethyl acetate (100 mL x 3 times), and the organic phases were combined and washed with saturated brine (200 mL x 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified on a silica gel column to yield 4.9 g of benzyl (4-(4-bromophenyl)bicyclo[2.2.2]octan-1-yl)carbamate.

[0816] MS (ESI) M / Z: 436.0 [M+23] + .

[0817] Step E: Dissolve benzyl (4-(4-bromophenyl)bicyclo[2.2.2]octan-1-yl)carbamate (4.6 g, 11.17 mmol) in 1,4-dioxane (55.8 mL) at 0°C. Then, add potassium carbonate (3.4 g, 24.64 mmol), trimethylboroxane (4.6 g, 36.96 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.91 g, 1.12 mmol) to the solution. Evacuate the air and replace it with nitrogen three times. Stir the reaction at 90°C for 6 hours.

[0818] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was filtered and the filter cake was rinsed with ethyl acetate (150 mL x 2). The filtrate was quenched with water (250 mL), and the mixture was extracted with ethyl acetate (150 mL x 3). The organic phases were combined and washed with saturated sodium chloride solution (200 mL x 2). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 2.76 g of benzyl(4-(p-tolyl)bicyclo[2.2.2]octan-1-yl)carbamate.

[0819] MS (ESI) M / Z: 372.0 [M+23] + .

[0820] Step F: Dissolve benzyl (4-(p-tolyl)bicyclo[2.2.2]octan-1-yl)carbamate (2.56 g, 7.34 mmol) in carbon tetrachloride (48.9 mL) at 0°C under nitrogen. N-bromosuccinimide (1.57 g, 8.80 mmol) and azobisisobutyronitrile (120 mg, 0.73 mmol) were then added to the solution. The reaction was stirred at 70°C for 3 hours.

[0821] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was filtered and the filter cake was rinsed with dichloromethane (60 mL x 2). The filtrate was quenched with water (100 mL), and the mixture was extracted with dichloromethane (80 mL x 3). The organic phases were combined and washed with saturated aqueous sodium chloride solution (100 mL x 2). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 520 mg of benzyl (4-(4-(bromomethyl)phenyl)bicyclo[2.2.2]octan-1-yl)carbamate.

[0822] MS (ESI) M / Z: 450.2 [M+23] + .

[0823] Step G: At -30°C under nitrogen, dissolve tert-butyl (R)-3-(2-((S)-4-benzyl-2-oxooxazolidin-3-yl)-2-oxoethyl)pyrrolidine-1-carboxylate (339 mg, 0.79 mmol) in tetrahydrofuran (1.9 mL). Then, add 1M lithium bistrimethylsilylamide (1 mL, 1.03 mmol) to the solution and stir for 0.5 hour. Then, slowly add a solution of benzyl (4-(4-(bromomethyl)phenyl)bicyclo[2.2.2]octan-1-yl)carbamate (410 mg, 0.96 mol) in tetrahydrofuran (1 mL) dropwise and stir for 1 hour. Then, warm the reaction system to 0°C and continue stirring for 2 hours.

[0824] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was slowly added to an ice-cold saturated ammonium chloride solution (20 mL) to quench the mixture. The mixture was extracted with ethyl acetate (15 mL × 3 times), and the organic phases were combined and washed with saturated brine (20 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified on a silica gel column to yield 260 mg of tert-butyl (R)-3-((S)-1-(S)-4-benzyl-2-oxooxazolidin-3-yl)-3-(4-(((benzyloxy)carbonyl)amino)bicyclo[2.2.2]octan-1-yl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate.

[0825] Step H: Tert-butyl (R)-3-((S)-1-(S)-4-benzyl-2-oxooxazolidin-3-yl)-3-(4-(((benzyloxy)carbonyl)amino)bicyclo[2.2.2]octan-1-yl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (200 mg, 0.27 mmol) was dissolved in tetrahydrofuran (7.2 mL) at 0°C. A 33% aqueous solution of hydrogen peroxide (62 mg, 0.54 mmol) in water (0.62 mL) and a solution of lithium hydroxide monohydrate (17 mg, 0.41 mmol) in water (0.41 mL) were then slowly added dropwise to the solution. The reaction was stirred for 3 hours.

[0826] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was slowly quenched by the dropwise addition of an aqueous solution (0.1 mL) of sodium bisulfite (7 mg, 0.55 mmol) at 0°C. The mixture was extracted with ethyl acetate (10 mL × 3 times), and the organic phases were combined and washed with saturated brine (15 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. This afforded 230 mg of crude (S)-3-(4-(4-(((benzyloxy)carbonyl)amino)bicyclo[2.2.2]oct-1-yl)phenyl)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)propanoic acid.

[0827] MS (ESI) M / Z: 477.0 [M-99] + .

[0828] Step I: (S)-3-(4-(4-(((benzyloxy)carbonyl)amino)bicyclo[2.2.2]oct-1-yl)phenyl)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)propanoic acid (208 mg, 0.36 mmol) and tert-butyl N,N'-diisopropylcarbamate (253 mg, 1.26 mmol) were dissolved in tetrahydrofuran (4 mL) at room temperature under nitrogen. The reaction was stirred at 65°C for 16 hours.

[0829] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was filtered and the filter cake was rinsed with tetrahydrofuran (10 mL x 4). The filtrate was quenched with water (20 mL), and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined and washed with saturated aqueous sodium chloride solution (20 mL x 2). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 85 mg of tert-butyl (R)-3-((S)-3-(4-(4-(((benzyloxy)carbonyl)amino)bicyclo[2.2.2]octan-1-yl)phenyl)-1-(tert-butyloxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate.

[0830] Step J: Tert-butyl (R)-3-((S)-3-(4-(4-(((benzyloxy)carbonyl)amino)bicyclo[2.2.2]oct-1-yl)phenyl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (85 mg, 0.10 mmol) and 10% palladium on carbon (30 mg) were dissolved in isopropanol (6 mL) at room temperature. The hydrogen atmosphere was replaced by air under vacuum three times, and the reaction was stirred at room temperature for 16 hours.

[0831] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was filtered, the filter cake was rinsed with tetrahydrofuran (10 mL × 4 times), all the filtrates were combined and concentrated under reduced pressure to give 63 mg of (R)-3-((S)-3-(4-(4-aminobicyclo[2.2.2]oct-1-yl)phenyl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester.

[0832] MS (ESI) M / Z: 521.5 [M+23] + .

[0833] Step K: (R)-tert-Butyl 3-((S)-3-(4-(4-aminobicyclo[2.2.2]octan-1-yl)phenyl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (58 mg, 0.12 mmol), (R)-tert-Butyl 3-((S)-3-(3-(bromomethyl)phenyl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (190 mg, 0.41 mmol), potassium carbonate (48 mg, 0.35 mmol), and potassium iodide (68 mg, 0.41 mmol) were dissolved in acetonitrile (4 mL) at room temperature under nitrogen. The reaction was then stirred at 40°C for 16 hours.

[0834] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was slowly added to an ice-water solution (10 mL) to quench the reaction. The mixture was extracted with ethyl acetate (10 mL × 3 times), and the organic phases were combined and washed with saturated brine (10 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 67 mg of 3,3'-di-tert-butyl((2S,2'S)-(((4-(4-(((S)-3-(tert-butyloxy)-2-((R)-1-(tert-butyloxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)bicyclo[2.2.2]octan-1-yl)azepinediyl)bis(methylene)bis(3,1-phenylene)bis(3-(tert-butyloxy)-3-hydroxypropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate).

[0835] Step L: At room temperature, under nitrogen protection, 3,3'-di-tert-butyl((2S,2'S)-(((4-(4-(((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)bicyclo[2.2.2]octan-1-yl)azepinediyl)bis(methylene)bis(3,1-phenylene)bis(3-(tert-butoxy)-3-hydroxypropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate) (64 mg, 0.05 mmol) was dissolved in dry dichloromethane (2 mL). Subsequently, 4M hydrochloric acid-1,4-dioxane (1 mL) was slowly added dropwise to the above solution. The reaction system was then stirred at room temperature for 16 hours.

[0836] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was filtered, and the filter cake was rinsed with dichloromethane (10 mL×2 times). The filter cake was collected and lyophilized to obtain 40 mg of (2S,2'S)-3,3'-(1S,4S)-4-(3-(((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)phenyl)cyclohexyl)nitrogendiyl)bis(methylene)bis(3,1-phenylene))bis(2-(((R)-pyrrolidin-3-yl)propionic acid) hydrochloride.

[0837] MS (ESI) M / Z: 805.4 [M+H] + .

[0838] 1H NMR(400MHz,D2O)δ7.32(d,J=8.4Hz,2H),7.24-7.08(m,6H),6.95-6.84(m,2H),6.7 4(s,1H),6.69(s,1H),4.77-4.72(m,2H),4.15-3.95(m,2H),3.61-3.45(m,3H),3.4 4-3.30(m,3H),3.26-3.13(m,3H),3.07-2.93(m,3H),2.90-2.77(m,2H),2.76-2.57 (m,7H),2.56-2.38(m,3H),2.32-2.19(m,6H),2.18-1.94(m,9H),1.79-1.64(m,3H).

[0839] Example 264

[0840] (2S,2'S)-3,3'-(((3-((3-carboxy-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-2-yl)methyl)benzyl)nitrogendiyl)bis(methylene)bis(3,1-phenylene))bis(2-(((R)-pyrrolidin-3-yl)propanoic acid)

[0841] The synthesis of Example 264 was based on Example 263.

[0842] MS (ESI) M / Z: 749.4 [M+H] + .

[0843] 1 H NMR(400MHz,D2O)δ7.39-7.25(m,5H),7.23-7.15(m,2H),7.12-7.02(m,5H ),5.65(s,2H),4.33-4.16(m,8H),3.63-3.50(m,2H),3.46-3.33(m,4H),3. 27-3.14(m,2H),3.09-2.96(m,4H),2.93-2.84(m,2H),2.83-2.74(m,2H),2 .73-2.64(m,2H),2.61-2.43(m,2H),2.22-2.03(m,2H),1.81-1.63(m,2H).

[0844] Example 287

[0845] (2S,2'S)-3,3'-(((((7-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)methoxy)azepinediyl)bis(methylene))bis(3,1-phenylene))bis(2-((R)-pyrrolidin-3-yl)propanoic acid)

[0846] It can also be prepared according to the following steps:

[0847] Reaction route:

[0848] Steps:

[0849] Step A: Dissolve tert-butyl (R)-3-((S)-3-(8-bromo-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (350 mg, 0.69 mmol), 3-oxobenzo[d]isothiazole-2(3H)-carbaldehyde 1,1-dioxide (361 mg, 1.71 mmol), palladium acetate (31 mg, 0.14 mmol), 1,4-bis(diphenylphosphino)butane (58 mg, 0.14 mmol), sodium carbonate (218 mg, 2.06 mmol), and triethylsilane (160 mg, 1.37 mmol) in N,N-dimethylformamide (3.5 mL) at room temperature. The atmosphere was replaced with nitrogen under vacuum three times, and the reaction was stirred at 75°C for 16 hours.

[0850] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was added to ice water (30 mL) to quench the mixture. The mixture was extracted with ethyl acetate (20 mL × 3 times), and the organic phases were combined and washed with saturated brine (30 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 50 mg of tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(8-formyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate.

[0851] MS (ESI) M / Z: 484.2 [M+23] + .

[0852] Step B: In an ice-water bath under nitrogen, dissolve tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(8-formyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (50 mg, 0.11 mmol) in methanol (0.6 mL). Then, slowly add sodium borohydride (6 mg, 0.16 mmol). The reaction system is then stirred at room temperature for 1 hour.

[0853] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was added to ice water (30 mL) to quench the mixture. The mixture was extracted with ethyl acetate (20 mL × 3 times), and the organic phases were combined and washed with saturated brine (30 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 44 mg of tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(8-(hydroxymethyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate.

[0854] MS (ESI) M / Z: 486.2 [M+23] + .

[0855] Step C: In an ice-water bath under nitrogen, tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(8-(hydroxymethyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (44 mg, 0.1 mmol), 2-hydroxyisoindole-1,3-dione (24 mg, 0.15 mmol), and triphenylphosphine (66 mg, 0.25 mmol) were dissolved in dry tetrahydrofuran (0.5 mL). Diisopropyl azodicarboxylate (51 mg, 0.25 mmol) was then slowly added dropwise to the solution. The reaction was stirred at room temperature for 3 hours.

[0856] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched by adding ice water (30 mL). The mixture was extracted with ethyl acetate (20 mL × 3 times), and the organic phases were combined and washed with saturated brine (30 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 45 mg of tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(8-(((1,3-dioxoisoindol-2-yl)oxy)methyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate.

[0857] MS (ESI) M / Z: 631.2 [M+23] + .

[0858] Step D: Under nitrogen at room temperature, tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(8-(((1,3-dioxoisoindol-2-yl)oxy)methyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (45 mg, 0.07 mmol) was dissolved in ethanol (0.4 mL). Hydrazine hydrate (18 mg, 0.35 mmol) was then added to the solution. The reaction was stirred at 80°C for 1 hour.

[0859] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 20 mg of tert-butyl (R)-3-((S)-3-(8-((aminooxy)methyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate.

[0860] MS (ESI) M / Z: 479.2 [M+H] + .

[0861] Step E: (R)-tert-Butyl 3-((S)-3-(8-((aminooxy)methyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (20 mg, 0.04 mmol), (R)-tert-Butyl 3-((S)-3-(3-(bromomethyl)phenyl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (47 mg, 0.1 mmol), potassium carbonate (17 mg, 0.12 mmol), and potassium iodide (17 mg, 0.1 mmol) were dissolved in acetonitrile (1.3 mL) at room temperature under nitrogen. The reaction was then stirred at 50°C for 16 hours.

[0862] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was added to ice water (30 mL) for quenching, and the mixture was extracted with ethyl acetate (20 mL × 3 times). The organic phases were combined and washed with saturated brine (30 mL × 2 times), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 25 mg of di-tert-butyl 3,3'-((2S,2'S)-(((((7-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)methoxy)azepinediyl)bis(methylene))bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxypropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate).

[0863] MS (ESI) M / Z: 1253.6 [M+H] + .

[0864] Step F: Di-tert-butyl 3,3'-((2S,2'S)-(((((7-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)methoxy)azepinediyl)bis(methylene))bis(3,1-phenylene))bis(3-(tert-butyloxy)-3-oxypropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate) (25 mg, 0.02 mmol) was dissolved in 4M hydrochloric acid-1,4-dioxane (0.5 mL) under nitrogen at room temperature. The reaction was stirred for 4 hours.

[0865] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was filtered. The resulting residual solid was rinsed with dichloromethane (10 mL x 2). The filter cake was purified by a neutral reverse-phase column (water / acetonitrile) and lyophilized to obtain 8.6 mg of (2S,2'S)-3,3'-(((((7-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)methoxy)azepinediyl)bis(methylene))bis(3,1-phenylene))bis(2-((R)-pyrrolidin-3-yl)propanoic acid) hydrochloride.

[0866] MS (ESI) M / Z: 785.5 [M+H] + .

[0867] 1H NMR(400MHz,D2O)δ7.34-7.25(m,2H),7.24-7.14(m,6H),6.64(s,1H),6.10(s,1H),4.27-3.80(m,10H),3.58-3.43(m,3H),3.42 -3.30(m,3H),3.25-3.13(m,3H),3.05-2.92(m,3H),2.90-2.76(m,4H),2.75-2.38(m,8H),2.19-2.01(m,3H),1.80-1.60(m,3H).

[0868] Example 251

[0869] (2S,2'S)-3,3'-(((4-(3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)phenyl)bicyclo[2.2.2]oct-1-yl)azinediyl)bis(methylene)bis(3,1-phenylene))bis(2-(((R)-pyrrolidin-3-yl)propanoic acid)

[0870] The synthesis of Example 251 refers to Example 262.

[0871] MS (ESI) M / Z: 403.3 [M / 2+H] + .

[0872] 1 H NMR(400MHz,D2O)δ7.30-7.16(m,2H),7.14(s,1H),7.12-7.04(m,4H),7.00(d,J=6.8Hz,1H) ,6.89-6.75(m,2H),6.70(s,1H),6.61(s,1H),4.60-4.56(m,2H),4.06-3.98(m,2H),3.53-3 .38(m,3H),3.37-3.23(m,3H),3.21-3.05(m,3H),3.00-2.89(m,3H),2.86-2.70(m,2H),2.6 7-2.52(m,7H),2.50-2.31(m,3H),2.23-2.00(m,9H),1.97-1.86(m,6H),1.71-1.55(m,3H).

[0873] Example 225

[0874] (2S,2'S)-3,3'-((((2-(3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)phenyl)-2-azaspiro[3.3]heptane-6-yl)azadiyl)bis(methylene))bis(3,1-phenylene))bis(2-((R)-pyrrolidin-3-yl)propanoic acid)

[0875] The synthesis of Example 225 was carried out with reference to Example 216.

[0876] MS (ESI) M / Z: 396.8 [M / 2+H] + .

[0877] 1 H NMR(400MHz,D2O)δ7.74-7.28(m,5H),7.27-7.19(m,3H),7.18-7.04(m,4H), 4.57-4.47(m,2H),4.45-4.34(s,2H),4.26-4.05(m,4H),3.93-3.83(m,1H), 3.64-3.53(m,3H),3.45-3.32(m,3H),3.29-3.16(m,3H),3.11-2.99(m,3H), 2.97-2.66(m,10H),2.63-2.43(m,6H),2.21-2.08(m,3H),1.81-1.65(m,3H).

[0878] Example 152

[0879] (2S,2'S)-3,3'-((2-((4-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)phenethyl)amino)propane-1,3-diyl)bis(3,1-phenylene))bis(2-(R)pyrrolidin-3-ylpropanoic acid)

[0880] The synthesis of Example 152 refers to Example 154.

[0881] MS (ESI) M / Z: 370.3 [M / 2+H] + .

[0882] 1H NMR(400MHz,D2O)δ7.28-7.17(m,2H),7.16-7.06(m,4H),7.04-6.91(m,6H),3.73-3.63(m,1H),3.60-3.49(m,3H),3.43-3.3 3(m,3H),3.27-3.11(m,5H),3.07-2.91(m,5H),2.90-2.61(m,13H),2.58-2.42(m,3H),2.20-2.04(m,3H),1.78-1.63(m,3H).

[0883] Example 168

[0884] (2S,2'S)-3,3'-((2-((3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)benzyl)oxy)propane-1,3-diyl)bis(3,1-phenylene))bis(2-(R)pyrrolidin-3-yl)propanoic acid)

[0885] It can also be prepared according to the following steps:

[0886] Reaction route:

[0887] Steps:

[0888] Step A: Dissolve 1-bromo-3-(chloromethyl)benzene (10 g, 48.67 mmol) and 1-(isocyanomethyl)sulfonyl-4-methylbenzene (4.75 g, 24.33 mmol) in dichloromethane (300 mL) at 0°C. Then, slowly add sodium hydroxide (90 g, 2.3 mol) in water (300 mL) dropwise to the solution. The reaction mixture is stirred at 35°C for 16 hours.

[0889] After LCMS monitoring indicated the disappearance of the starting material, the reaction mixture was slowly added to an ice-water solution (300 mL) to quench the reaction. The mixture was extracted with dichloromethane (200 mL x 3), and the organic phases were combined and washed with saturated brine (100 mL x 2). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified on a silica gel column to yield 6.8 g of 1,3-bis(3-bromophenyl)propan-2-one.

[0890] Step B: At 0°C under nitrogen, dissolve 1,3-bis(3-bromophenyl)propan-2-one (6.8 g, 18.58 mmol) in methanol (100 mL). Then, slowly add sodium borohydride (0.74 g, 19.18 mmol) to the solution. The reaction system is then stirred at room temperature for 0.5 hours.

[0891] After LCMS monitoring indicated the disappearance of the starting material, the reaction mixture was slowly added to an ice-water solution (80 mL) to quench the reaction. The mixture was extracted with dichloromethane (30 mL x 3), and the organic phases were combined and washed with saturated brine (20 mL x 2). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified on a silica gel column to yield 5 g of 1,3-bis(3-bromophenyl)propan-2-ol.

[0892] Step C: Dissolve 1,3-bis(3-bromophenyl)propan-2-ol (5 g, 13.59 mmol) in dry N,N-dimethylformamide (71 mL) at 0°C under nitrogen. Add 60 wt% sodium hydride (1.1 g, 27.17 mmol) to the solution and stir for 0.5 hour. Then, add benzyl bromide (3.6 g, 20.38 mmol) dropwise. Warm the mixture to room temperature and continue stirring for 1.5 hours.

[0893] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was slowly added to an ice-water solution (400 mL) to quench the reaction. The mixture was extracted with ethyl acetate (70 mL x 3), and the organic phases were combined and washed with saturated brine (50 mL x 2). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified on a silica gel column to yield 5 g of 3,3'-(2-(benzyloxy)propane-1,3-diyl)bis(bromobenzene).

[0894] Step D: Dissolve 3,3'-(2-(benzyloxy)propane-1,3-diyl)bis(bromobenzene) (4.6 g, 10.04 mmol) in dry tetrahydrofuran (50 mL) at -78°C under nitrogen. Slowly add 2.5 M n-butyllithium (12 mL, 30.13 mmol) dropwise to the solution and stir for 0.5 hour. Then, add dry N,N-dimethylformamide (2.2 g, 30.13 mmol) dropwise and continue stirring for 0.5 hour.

[0895] After LCMS monitoring indicated the disappearance of the starting material, the reaction mixture was slowly added to an ice-water solution (80 mL) to quench the reaction. The mixture was extracted with ethyl acetate (30 mL x 3), and the organic phases were combined and washed with saturated brine (20 mL x 2). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified on a silica gel column to yield 2.6 g of 3,3'-(2-(benzyloxy)propane-1,3-diyl)dibenzaldehyde.

[0896] 1H NMR (400MHz, DMSO-d6) δ9.98 (s, 2H), 7.80-7.72 (m, 4H), 7.60-7.55 (m, 2H), 7.54 (t, J = 7.8Hz, 2H),7.23-7.16(m,3H),7.04-6.96(m,2H),4.37(s,2H),4.00-3.89(m,1H),3.00-2.81(m,4H).

[0897] Step E: At 0°C under nitrogen, dissolve 3,3'-(2-(benzyloxy)propane-1,3-diyl)benzaldehyde (2.6 g, 7.26 mmol) in methanol (36 mL). Then, slowly add sodium borohydride (0.27 g, 7.26 mmol) to the solution. The reaction mixture is stirred at room temperature for 0.5 hours.

[0898] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was slowly added to an ice-water solution (60 mL) to quench the mixture. The mixture was extracted with dichloromethane (30 mL x 3), and the organic phases were combined and washed with saturated brine (20 mL x 2). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified on a silica gel column to yield 2.5 g of (2-(benzyloxy)propane-1,3-diyl)bis(3,1-phenylene))dimethanol.

[0899] MS (ESI) M / Z: 385.2 [M+23] + .

[0900] Step F: Dissolve (2-(benzyloxy)propane-1,3-diyl)bis(3,1-phenylene)dimethanol (2.5 g, 6.9 mmol) and triphenylphosphine (5.4 g, 20.7 mmol) in dry dichloromethane (35 mL) at 0°C under nitrogen. Then, slowly add carbon tetrabromide (6.88 g, 20.7 mmol). The reaction mixture is stirred at room temperature for 1 hour.

[0901] After LCMS monitoring indicated the disappearance of the starting material, the reaction mixture was slowly added to an ice-water solution (60 mL) to quench the reaction. The mixture was extracted with dichloromethane (30 mL x 3), and the organic phases were combined and washed with saturated brine (20 mL x 2). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified on a silica gel column to yield 2.3 g of 3,3'-(2-(benzyloxy)propane-1,3-diyl)bis((bromomethyl)benzene).

[0902] MS (ESI) M / Z: 509.0 [M+23] + .

[0903] Step G: Dissolve tert-butyl (R)-3-(2-((S)-4-benzyl-2-oxooxazolidin-3-yl)-2-oxoethyl)pyrrolidine-1-carboxylate (1.6 g, 4.12 mmol) in dry tetrahydrofuran (0.8 mL) at -30°C. Slowly add 1M lithium bistrimethylsilylamide (2 mL, 2.06 mmol) dropwise to the solution and stir for 0.5 hour. Then, slowly add a solution of 3,3'-(2-(benzyloxy)propane-1,3-diyl)bis((bromomethyl)benzene) (1 g, 2.06 mmol) in tetrahydrofuran (1.2 mL) dropwise and stir for 1 hour. The reaction mixture is then warmed to 0°C and stirred for 2 hours.

[0904] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was slowly added to an ice-cold saturated aqueous ammonium chloride solution (50 mL) to quench the mixture. The mixture was extracted with ethyl acetate (20 mL × 3 times), and the organic phases were combined and washed with saturated brine (10 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 740 mg of 3,3'-((2S,2'S)-((2-(benzyloxy)propane-1,3-diyl)bis(3,1-phenylene))bis(3-(((S)-4-benzyl-2-oxooxazolidin-3-yl)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate).

[0905] Step H: At 0°C under nitrogen, 3,3'-((2S,2'S)-((2-(benzyloxy)propane-1,3-diyl)bis(3,1-phenylene))bis(3-(((S)-4-benzyl-2-oxooxazolidin-3-yl)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate) (740 mg, 0.67 mmol) was dissolved in tetrahydrofuran (5 mL). Subsequently, a solution of 33% hydrogen peroxide (232 mg, 2.015 mmol) in water (2.3 mL) and a solution of lithium hydroxide monohydrate (84 mg, 2.015 mmol) in water (2 mL) were slowly added dropwise to the above solution. The reaction system was then stirred for 2 hours.

[0906] After LCMS monitoring showed the disappearance of the starting material, a solution of sodium bisulfite (286 mg, 2.07 mmol) in water (5 mL) was slowly added to the reaction mixture. The mixture was adjusted to pH > 12 with saturated aqueous sodium hydroxide solution and then extracted with methyl tert-butyl ether (20 mL × 3 times). The resulting aqueous phase was adjusted to pH < 3 with dilute hydrochloric acid and extracted with ethyl acetate (20 mL × 3 times). The organic phases were combined and washed with saturated brine (5 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield 450 mg of (2S,2'S)-3,3'-((2-(benzyloxy)propane-1,3-diyl)bis(3,1-phenylene))bis(2-(((R)1-(tert-butoxycarbonyl)pyrrolidin-3-yl)propanoic acid).

[0907] MS (ESI) M / Z: 785.4 [M+H] + .

[0908] Step I: (2S,2'S)-3,3'-((2-(benzyloxy)propane-1,3-diyl)bis(3,1-phenylene))bis(2-(((R)1-(tert-butoxycarbonyl)pyrrolidin-3-yl)propanoic acid) (450 mg, 0.57 mmol) and tert-butyl N,N'-diisopropylcarbamate (1.4 g, 4.01 mmol) were dissolved in tetrahydrofuran (3 mL) at room temperature under nitrogen. The reaction was then stirred at 65 °C for 16 h.

[0909] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was filtered, the filter cake was rinsed with tetrahydrofuran (20 mL x 3), and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 180 mg of 3,3'-di-tert-butyl((2S,2'S)-((2-(benzyloxy)propane-1,3-diyl)bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate).

[0910] MS (ESI) M / Z: 898.2 [M+H] + .

[0911] Step J: 3,3'-di-tert-butyl((2S,2'S)-((2-(benzyloxy)propane-1,3-diyl)bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate) (180 mg, 0.20 mmol) and palladium hydroxide (150 mg) were dissolved in methanol (20 mL) at room temperature. The hydrogen atmosphere was replaced under vacuum three times, and the reaction system was stirred at 60°C for 16 hours.

[0912] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was filtered, the filter cake was rinsed with methanol (20 mL x 3), and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 100 mg of 3,3'-((2S,2'S)-((2-hydroxypropane-1,3-diyl)bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate).

[0913] MS (ESI) M / Z: 808.0 [M+H] + .

[0914] Step K: 3,3'-((2S,2'S)-((2-hydroxypropane-1,3-diyl)bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate) (100 mg, 0.12 mmol) was dissolved in dry N,N-dimethylformamide (3 mL) at room temperature under nitrogen. 60 wt% sodium hydride (10 mg, 0.25 mmol) was then added to the solution and stirred for 0.5 h. Then, tert-butyl (R)-3-((S)-3-(3-(bromomethyl)phenyl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (117 mg, 0.25 mmol) was added, the temperature was raised to 50°C, and stirring was continued for 24 h.

[0915] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was slowly added to an ice-water solution (40 mL) to quench the reaction. The mixture was extracted with ethyl acetate (10 mL × 3 times), and the organic phases were combined and washed with saturated brine (10 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 20 mg of 3,3'-di-tert-butyl((2S,2'S)-(2-(((3-((S)-3(tert-butyloxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)benzyl)oxy)propane-1,3-diyl)bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxypropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate).

[0916] MS (ESI) M / Z: 1195.4 [M+H] + .

[0917] Step L: At room temperature, under nitrogen protection, 3,3'-di-tert-butyl((2S,2'S)-(2-(((3-((S)-3(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)benzyl)oxy)propane-1,3-diyl)bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxypropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate) (20 mg, 0.017 mmol) was dissolved in dry dichloromethane (0.5 mL). Subsequently, 4M hydrochloric acid-1,4-dioxane (1 mL) was slowly added dropwise to the above solution. The reaction system was then stirred for 16 hours.

[0918] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was filtered and the filter cake was rinsed with dichloromethane (10 mL x 2). The resulting filter cake was purified by a neutral reverse-phase column (water / acetonitrile) and lyophilized to obtain 5.1 mg of (2S,2'S)-3,3'-((2-((3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)benzyl)oxy)propane-1,3-diyl)bis(3,1-phenylene))bis(2-(R)pyrrolidin-3-yl)propanoic acid) hydrochloride.

[0919] MS (ESI) M / Z: 726.5 [M+H] + .

[0920] 1 H NMR(400MHz,D2O)δ7.33-6.92(m,10H),6.75-6.64(m,1H),6.62-6.50(m ,1H),4.17-3.95(m,2H),3.92-3.75(m,1H),3.57-3.45(m,1H),3.44-3.2 7(m,5H),3.25-3.10(m,3H),3.05-2.90(m,4H),2.89-2.56(m,12H),2.5 5-2.37(m,3H),2.35-2.16(m,2H),2.16-2.04(m,1H),1.80-1.60(m,3H).

[0921] Example 270

[0922] (2S,2'S)-3,3'-(1S,4S)-4-(3-(((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)phenyl)cyclohexyl)nitrodiyl)bis(methylene)bis(3,1-phenylene))bis(2-(((R)-pyrrolidin-3-yl)propanoic acid)

[0923] The synthesis of Example 270 was based on Example 269.

[0924] MS (ESI) M / Z: 390.3 [M / 2+H] + .

[0925] 1 H NMR(400MHz,D2O)δ7.41-7.00(m,12H),4.53-4.39(m,2H),4.24-4.12(m,2H),3.63-3.48(m,3H),3.44-3.31(m,3H),3.30-3.14(m,4H) ,3.09-2.96(m,3H),2.95-2.63(m,9H),2.62-2.43(m,4H),2.29-2.05(m,5H),2.04-1.82(m,4H),1.78-1.62(m,3H),1.57-1.35(m,2H).

[0926] Example 289

[0927] (2S,2'S)-3,3'-((((2-(7-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)-2,3-dihydrobenzo[b][1,4]dioxol-5-yl)ethyl]azinediyl)bis(methylene))bis(3,1-phenylene))bis(2-((R)-pyrrolidin-3-yl)propanoic acid)

[0928] It can also be prepared according to the following steps:

[0929] Reaction route:

[0930] Steps:

[0931] Step A: At room temperature under nitrogen, tert-butyl (R)-3-((S)-3-(8-bromo-2,3-dihydrobenzo[b][1,4]dioxan-6-yl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (800 mg, 1.6 mmol), potassium vinyl trifluoroborate (543 mg, 4.06 mmol), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (64 mg, 0.16 mmol), potassium carbonate (435 mg, 3.12 mmol), and palladium acetate (35 mg, 0.16 mmol) were dissolved in 1,4-dioxane / water (8 mL / 1.5 mL). The reaction was then stirred at 90°C for 24 hours.

[0932] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was slowly added to an ice-water solution (100 mL) to quench the mixture. The mixed solution was extracted with ethyl acetate (20 mL × 3 times), and the organic phases were combined and washed with saturated brine (40 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column to obtain 360 mg of tert-butyl (R)-3-((S)-1-(tert-butoxy)-1-oxo-3-(8-vinyl-2,3-dihydrobenzo[b][1,4]dioxan-6-yl)propan-2-yl)pyrrolidine-1-carboxylate.

[0933] MS (ESI) M / Z: 482.3 [M+23] + .

[0934] Step B: At 0°C under nitrogen, dissolve tert-butyl (R)-3-((S)-1-(tert-butoxy)-1-oxo-3-(8-vinyl-2,3-dihydrobenzo[b][1,4]dioxan-6-yl)propan-2-yl)pyrrolidine-1-carboxylate (250 mg, 0.54 mmol) in dry tetrahydrofuran (2.5 mL). Then, add 0.5 M 9-borabicyclo[3.3.1]nonane (2.2 mL, 1.09 mmol) dropwise to the solution, warm to 60°C, and stir for 1 hour. Then, cool to 0°C, add 1 M aqueous sodium hydroxide (2.5 mL, 2.5 mmol) and hydrogen peroxide (2.5 mL), and warm to room temperature before stirring for 2 hours.

[0935] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was slowly added to an ice-water solution (40 mL) to quench the mixture. The mixed solution was extracted with ethyl acetate (20 mL × 3 times), and the organic phases were combined and washed with saturated brine (20 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 140 mg of (R)-3-((S)-1-(tert-butoxy)-3-(8-(2-hydroxyethyl)-2,3-dihydrobenzo[b][1,4]dioxan-6-yl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester.

[0936] MS (ESI) M / Z: 500.3 [M+23] + .

[0937] Step C: In an ice-water bath under nitrogen, tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(8-(2-hydroxyethyl)-2,3-dihydrobenzo[b][1,4]dioxan-6-yl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (200 mg, 0.42 mmol), isoindole-1,3-dione (92 mg, 0.63 mmol), and triphenylphosphine (220 mg, 0.84 mmol) were dissolved in dry tetrahydrofuran (6 mL). Diisopropyl azodicarboxylate (170 mg, 0.84 mmol) was then slowly added dropwise to the solution. The reaction was stirred at room temperature for 1 hour.

[0938] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was added to ice water (30 mL) to quench the reaction. The mixture was extracted with ethyl acetate (20 mL × 3 times), and the organic phases were combined and washed with saturated brine (30 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 178 mg of (R)-3-((S)-1-(tert-butyloxy)-3-(8-(2-(1,3-dioxoisoindol-2-yl)ethyl)-2,3-dihydrobenzo[b][1,4]dioxol-6-yl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester.

[0939] MS (ESI) M / Z: 629.2 [M+23] + .

[0940] Step D: Under nitrogen at room temperature, tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(8-(2-(1,3-dioxoisoindol-2-yl)ethyl)-2,3-dihydrobenzo[b][1,4]dioxol-6-yl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (178 mg, 0.29 mmol) was dissolved in ethanol (2 mL). Hydrazine hydrate (73 mg, 1.47 mmol) was then added to the solution. The reaction was stirred at 85°C for 1 hour.

[0941] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give 98 mg of tert-butyl (R)-3-((S)-3-(8-(2-aminoethyl)-2,3-dihydrobenzo[b][1,4]dioxan-6-yl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate.

[0942] MS (ESI) M / Z: 477.2 [M+H] + .

[0943] Step E: (R)-tert-Butyl 3-((S)-3-(8-(2-aminoethyl)-2,3-dihydrobenzo[b][1,4]dioxan-6-yl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (60 mg, 0.12 mmol), (R)-tert-Butyl 3-((S)-3-(3-(bromomethyl)phenyl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (130 mg, 0.28 mmol), potassium carbonate (34.8 mg, 0.25 mmol), and potassium iodide (42 mg, 0.25 mmol) were dissolved in acetonitrile (1.2 mL) at room temperature under nitrogen. The reaction was then stirred at 50°C for 16 hours.

[0944] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was added to ice water (30 mL) for quenching, and the mixture was extracted with ethyl acetate (20 mL × 3 times). The organic phases were combined and washed with saturated brine (30 mL × 2 times), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 100 mg of 3,3'-di-tert-butyl((2S,2'S)-(((2-(7-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)-2,3-dihydrobenzo[b][1,4]dioxolan-5-yl)ethyl)azinediyl)bis(methylene)bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxypropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate).

[0945] MS (ESI) M / Z: 1252.4 [M+H] + .

[0946] Step F: 3,3'-di-tert-butyl((2S,2'S)-(((2-(7-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)-2,3-dihydrobenzo[b][1,4]dioxolan-5-yl)ethyl)azinediyl)bis(methylene)bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxypropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate) (100 mg, 0.08 mmol) was dissolved in 4M hydrochloric acid-1,4-dioxane solution / dichloromethane (1 mL / 1 mL) at room temperature under nitrogen. The reaction system was then stirred for 4 hours.

[0947] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was filtered, and the resulting filter cake was rinsed with dichloromethane (10 mL × 2 times). The filter cake was collected and purified by a neutral (mobile phase: water / acetonitrile) reverse phase column and lyophilized to obtain 49.44 mg of (2S,2'S)-3,3'-((((2-(7-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)-2,3-dihydrobenzo[b][1,4]dioxol-5-yl)ethyl]azinediyl)bis(methylene))bis(3,1-phenylene))bis(2-((R)-pyrrolidin-3-yl)propanoic acid) hydrochloride.

[0948] MS (ESI) M / Z: 783.5 [M+H] + .

[0949] 1 H NMR(400MHz,D2O)δ7.38(t,J=7.4Hz,2H),7.32(d,J=7.6Hz,2H),7.24(d,J=7.6Hz ,2H),7.16(s,2H),6.63(s,1H),6.45(s,1H),4.44-4.20(m,4H),4.10(s,2H),3.9 8(s,2H),3.62-3.46(m,3H),3.43-3.31(m,3H),3.24-3.12(m,5H),3.08-2.76(m, 9H),2.75-2.56(m,5H),2.55-2.39(m,3H),2.17-2.02(m,3H),1.77-1.61(m,3H).

[0950] Example 268

[0951] (S)-3-(3-(6-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)-3-(3-((S)-2-carboxy)-2-((R)-pyrrolidin-3-yl)ethyl)benzyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)-2-((R)-pyrrolidin-3-yl)propanoic acid

[0952] The synthesis of Example 268 was carried out with reference to Example 123.

[0953] MS (ESI) M / Z: 725.4 [M+H] + .

[0954] 1H NMR(400MHz,D2O)δ7.49(t,J=7.6Hz,1H),7.36-7.25(m,4H),7.19-7.10(m,2H),7.08(s,1H),6.94(s,2H),6.91(s,1H),5.16-5.01(m,2H),3.59 -3.51(m,1H),3.50-3.29(m,5H),3.22(s,3H),3.07-2.73(m,10H),2.71 -2.60(m,2H),2.59-2.36(m,3H),2.23-2.01(m,3H),1.80-1.60(m,3H).

[0955] Example 267

[0956] (S)-2-Amino-3-(3-(((3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)benzyl)(3-((R)-2-carboxy-2-((S)-pyrrolidin-3-yl)ethyl)benzyl)amino)methyl)phenyl)propanoic acid

[0957] The synthesis of Example 267 was carried out with reference to Example 246.

[0958] MS (ESI) M / Z: 658.3 [M+H] + .

[0959] 1 H NMR(400MHz,D2O)δ7.44-7.28(m,6H),7.25-7.08(m,6H),4.31-4.18(m, 6H),3.95(t,J=6.4Hz,1H),3.62-3.52(m,2H),3.43-3.32(m,2H),3.26-3 .11(m,4H),3.07-2.99(m,2H),2.94-2.86(m,2H),2.86-2.75(m,2H),2.7 2-2.62(m,2H),2.59-2.45(m,2H),2.20-2.02(m,2H),1.80-1.63(m,2H).

[0960] Example 49

[0961] 4,4'-((((4-((R)-2-carboxy-2-((S)-pyrrolidin-3-yl)ethyl)benzyl)azadiyl)bis(methylene))bis(3,1-phenylene))bis(methylene))bis(piperidine-4-carboxylic acid)

[0962] It can also be prepared according to the following steps:

[0963] Reaction route:

[0964] Steps:

[0965] Step A: Dissolve 1-tert-butyl 4-methylpiperidinyl 1,4-dicarboxylate (5 g, 20.6 mmol) in dry tetrahydrofuran (20.0 mL) at -30°C under nitrogen. Slowly add 1M lithium bistrimethylsilylamide (24.7 mL, 24.7 mmol) dropwise to the solution and stir for 30 minutes. Then, slowly add a solution of 1-bromo-3-(bromomethyl)benzene (6.16 g, 24.7 mmol) in tetrahydrofuran (10.8 mL) dropwise. Stir for 30 minutes, then warm to 0°C and continue stirring for 2 hours.

[0966] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was poured into an ice-cold saturated ammonium chloride solution (100 mL) for quenching. The mixture was extracted with ethyl acetate (200 mL × 3 times), and the organic phases were combined and washed with saturated brine (200 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. 6.2 g of 1-tert-butyl 4-methyl-4-[(3-bromophenyl)methyl]piperidine-1,4-dicarboxylate was obtained.

[0967] MS (ESI) M / Z: 434.0 [M+23] + .

[0968] Step B: Dissolve 1-tert-butyl 4-methyl-4-[(3-bromophenyl)methyl]piperidine-1,4-dicarboxylate (1.2 g, 2.9 mmol) in methanol (24 mL) at 0°C. Then, slowly add an aqueous solution (8 mL) of lithium hydroxide monohydrate (367 mg, 8.73 mmol) dropwise to the solution. The reaction system is then stirred at 65°C for 16 hours.

[0969] After LCMS monitoring showed the disappearance of the starting material, 1 M hydrochloric acid was added to the reaction solution to adjust the pH to ≤ 7. The mixture was extracted with ethyl acetate (100 mL x 4 times), and the organic phases were combined and washed with saturated brine (50 mL x 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 1.1 g of 4-[(3-bromophenyl)methyl]-1-[(tert-butoxy)carbonyl]piperidine-4-carboxylic acid.

[0970] MS (ESI) M / Z: 342.0 [M-55] + .

[0971] Step C: Dissolve 4-[(3-bromophenyl)methyl]-1-[(tert-butoxy)carbonyl]piperidine-4-carboxylic acid (1.1 g, 2.42 mmol) and 2-tert-butyl-1,3-diisopropylisourea (5.83 g, 29.1 mmol) in tetrahydrofuran (10 mL) at room temperature under nitrogen. The reaction mixture was stirred at 65°C for 16 hours.

[0972] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was filtered and the filter cake was rinsed with tetrahydrofuran (30 mL x 4). The filtrate was quenched with water (100 mL), and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined and washed with saturated sodium chloride solution (50 mL x 2). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 1.1 g of 1,4-di-tert-butyl 4-[(3-bromophenyl)methyl]piperidine-1,4-dicarboxylate.

[0973] MS (ESI) M / Z: 476.2 [M+23] + .

[0974] Step D: Dissolve 1,4-di-tert-butyl 4-[(3-bromophenyl)methyl]piperidine-1,4-dicarboxylate (1.1 g, 2.64 mmol), 3-oxobenzo[d]isothiazole-2(3H)-carbaldehyde 1,1-dioxide (1.39 g, 6.6 mmol), palladium acetate (119 mg, 0.53 mmol), 1,4-bis(diphenylphosphino)butane (225 mg, 0.53 mmol), sodium carbonate (839 mg, 7.92 mmol), and triethylsilane (614 mg, 5.28 mmol) in dry N,N-dimethylformamide (18 mL) at room temperature. Evacuate the air and replace with nitrogen three times. Stir the reaction at 75°C for 16 hours.

[0975] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was added to ice water (100 mL) for quenching. The mixture was extracted with ethyl acetate (60 mL × 3 times), and the organic phases were combined and washed with saturated brine (40 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 520 mg of 1,4-di-tert-butyl 4-[(3-formylphenyl)methyl]piperidine-1,4-dicarboxylate.

[0976] MS (ESI) M / Z: 426.2 [M+23] + .

[0977] Step E: Dissolve 1,4-di-tert-butyl 4-[(3-formylphenyl)methyl]piperidine-1,4-dicarboxylate (230 mg, 0.57 mmol) in isopropanol (5 mL) at room temperature under nitrogen. Add 3.5 M ammonia in isopropanol (1.28 mL, 4.47 mmol) and acetic acid (34 mg, 0.57 mmol) dropwise to the solution and stir for 1 hour. Then, add sodium cyanoborohydride (358 mg, 5.70 mmol), raise the temperature to 70°C, and continue stirring for 4 hours.

[0978] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was added to ice water (10 mL) to quench the reaction. The mixture was extracted with ethyl acetate (10 mL × 3 times), and the organic phases were combined and washed with saturated brine (10 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 100 mg of 1,4-di-tert-butyl 4-[(3-({[(3-[(1,4-bis[(tert-butoxy)carbonyl]piperidin-4-yl)methyl]phenyl)methyl]amino}methyl)phenyl)methyl]piperidine-1,4-dicarboxylate.

[0979] MS (ESI) M / Z: 792.4 [M+H] + .

[0980] Step F: 1,4-di-tert-butyl 4-[(3-({[(3-[(1,4-bis[(tert-butoxy)carbonyl]piperidin-4-yl)methyl]phenyl)methyl]amino}methyl)phenyl)methyl]piperidine-1,4-dicarboxylate (50 mg, 0.06 mmol), (3R)-tert-butyl 3-[(2S)-3-(3-(bromomethyl)phenyl)-1-(tert-butoxy)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (30 mg, 0.06 mmol), potassium carbonate (17 mg, 0.13 mmol), and potassium iodide (21 mg, 0.13 mmol) were dissolved in acetonitrile (3 mL) at room temperature. The reaction was stirred at 40 °C for 5 h.

[0981] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was quenched by adding ice water (10 mL). The mixture was extracted with ethyl acetate (10 mL × 3 times), and the organic phases were combined and washed with saturated brine (10 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 30 mg of 1,4-di-tert-butyl 4-[(3-({[(3-[(1,4-bis[(tert-butoxy)carbonyl]piperidin-4-yl)methyl]phenyl)methyl][(4-[(2R)-3-(tert-butoxy)-2-[(3S)-1-[(tert-butoxy)carbonyl]pyrrolidin-3-yl]-3-oxopropyl]phenyl)methyl]amino}methyl)phenyl)methyl]piperidine-1,4-dicarboxylate.

[0982] MS (ESI) M / Z: 540.4 [(M-100) / 2+H] + .

[0983] Step G: 1,4-di-tert-butyl 4-[(3-({[(3-[(1,4-bis[(tert-butoxy)carbonyl]piperidin-4-yl)methyl]phenyl)methyl][(4-[(2R)-3-(tert-butoxy)-2-[(3S)-1-[(tert-butoxy)carbonyl]pyrrolidin-3-yl]-3-oxopropyl]phenyl)methyl]amino}methyl)phenyl)methyl]piperidine-1,4-dicarboxylate (30 mg, 0.03 mmol) was dissolved in 4 M hydrochloric acid-1,4-dioxane (4 mL) at room temperature. The reaction was stirred for 4 hours.

[0984] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was filtered, the filter cake was rinsed with dichloromethane (10 mL×2 times), the filter cake was collected, and concentrated under reduced pressure to obtain 20 mg of 4,4'-((((4-((R)-2-carboxy-2-((S)-pyrrolidin-3-yl)ethyl)benzyl)azepinediyl)bis(methylene))bis(3,1-phenylene))bis(methylene))bis(piperidine-4-carboxylic acid) hydrochloride.

[0985] MS (ESI) M / Z: 711.4 [M+H] + .

[0986] 1H NMR(400MHz,D2O)δ7.39-7.28(m,4H),7.27-7.21(m,2H),7.21-7.11(m,4H),7.07(s,2H),4.25(s,6H),3.63-3.52(m,1H),3.45- 3.27(m,5H),3.26-3.14(s,1H),3.09-2.98(m,1H),2.97-2.64(m,11H),2.61-2.47(m,1H),2.24-2.03(m,5H),1.85-1.61(m,5H).

[0987] Example 303

[0988] (S)-3-(5-((((7-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)-2,3-dihydrobenzo[b][1),4]dioxin-5-yl)methyl)(3-((R)-2-carboxy-2-((S)-pyrrolidin-3-yl)ethyl)-4-methoxybenzyl)amino)methyl)-2-methoxyphenyl)-2-((R)-pyrrolidin-3-yl)propanoic acid

[0989] It can also be prepared according to the following steps:

[0990] Reaction route:

[0991] Steps:

[0992] Step A: Dissolve tert-butyl (3R)-3-(2-[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-2-oxoethyl)pyrrolidine-1-carboxylate (1 g, 2.7 mmol) in dry tetrahydrofuran (13 mL) at -30°C under nitrogen. Slowly add 1M lithium bistrimethylsilylamide (3.1 mL, 3.1 mmol) dropwise to the solution and stir for 30 minutes. Then, slowly add a solution of 4-bromo-2-(bromomethyl)-1-methoxybenzene (863 mg, 3.1 mol) in tetrahydrofuran (5 mL) dropwise. Stir for 30 minutes, then warm to 0°C and continue stirring for 2 hours.

[0993] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was poured into an ice-cold saturated ammonium chloride solution (100 mL) for quenching. The mixture was extracted with ethyl acetate (200 mL × 3 times), and the organic phases were combined and washed with saturated brine (200 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. This yielded 1.09 g of tert-butyl (3R)-3-[(2S)-1-[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-3-(4-bromo)-2-methoxyphenyl.

[0994] MS (ESI) M / Z: 609.2 [M+23] + .

[0995] Step B: Dissolve tert-butyl (3R)-3-[(2S)-1-[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-3-(4-bromo)-2-methoxyphenyl (1.09 g, 1.85 mmol) in tetrahydrofuran (15 mL) in an ice-water bath. Then, slowly add a 33% aqueous solution of hydrogen peroxide (3.2 mL, 2.78 mmol) and a solution of lithium hydroxide monohydrate (117 mg, 2.78 mmol) in water (3.2 mL) to the solution. Stir the reaction mixture for 4 hours.

[0996] After LCMS monitoring showed the disappearance of the starting material, sodium bisulfite solution (8 mL) was added to the reaction solution to quench it, and the pH was adjusted to >12 with saturated sodium hydroxide aqueous solution. The reaction mixture was extracted with methyl tert-butyl ether (100 mL × 4 times). The aqueous phase was then adjusted to pH = 3 with 8M hydrochloric acid solution and extracted with ethyl acetate (100 mL × 3 times). The organic phases were combined and washed with saturated brine (50 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 600 mg of (2S)-3-(5-bromo-2-methoxyphenyl)-2-[(3R)-1-[(tert-butoxy)carbonyl]pyrrolidin-3-yl]propanoic acid.

[0997] MS (ESI) M / Z: 450.0 [M+23] + .

[0998] Step C: (2S)-3-(5-bromo-2-methoxyphenyl)-2-[(3R)-1-[(tert-butoxy)carbonyl]pyrrolidin-3-yl]propanoic acid (600 mg, 1.40 mmol) and 2-tert-butyl-1,3-diisopropylisourea (2.8 g, 14 mmol) were dissolved in dry tetrahydrofuran (15 mL) under nitrogen at room temperature. The reaction was then stirred at 65°C for 4 hours.

[0999] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was filtered and the filter cake was rinsed with tetrahydrofuran (50 mL x 4). The filtrate was quenched with water (100 mL) and extracted with ethyl acetate (60 mL x 3). The organic phases were combined and washed with saturated brine (60 mL x 2). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 600 mg of tert-butyl (3R)-3-[(2S)-3-(5-bromo-2-methoxyphenyl)-1-(tert-butoxy)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate.

[1000] MS (ESI) M / Z: 506.2 [M+23] + .

[1001] Step D: Dissolve tert-butyl (3R)-3-[(2S)-3-(5-bromo-2-methoxyphenyl)-1-(tert-butoxy)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (600 mg, 1.24 mmol), 3-oxobenzo[d]isothiazole-2(3H)-carbaldehyde 1,1-dioxide (654.7 mg, 3.1 mmol), palladium acetate (56 mg, 0.25 mmol), 1,4-bis(diphenylphosphino)butane (106 mg, 0.25 mmol), sodium carbonate (394 mg, 3.72 mmol), and triethylsilane (288 mg, 2.48 mmol) in dry N,N-dimethylformamide (13 mL) at room temperature. The air was evacuated under vacuum three times to replace the atmosphere with nitrogen, and the reaction system was stirred at 75°C for 16 hours.

[1002] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was added to ice water (100 mL) for quenching. The mixture was extracted with ethyl acetate (60 mL × 3 times), and the organic phases were combined and washed with saturated brine (40 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 520 mg of 1,4-di-tert-butyl 4-[(3-formylphenyl)methyl]piperidine-1,4-dicarboxylate.

[1003] MS (ESI) M / Z: 456.2 [M+23] + .

[1004] Step E: Dissolve 1,4-di-tert-butyl 4-[(3-formylphenyl)methyl]piperidine-1,4-dicarboxylate (200 mg, 0.46 mmol) in isopropanol (5 mL) at room temperature under nitrogen. Add 3.5 M ammonia in isopropanol (1.27 mL, 4.47 mmol) and acetic acid (41 mg, 0.69 mmol) dropwise to the solution and stir for 1 hour. Then, add sodium cyanoborohydride (289 mg, 4.60 mmol), raise the temperature to 70°C, and continue stirring for 4 hours.

[1005] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was added to ice water (100 mL) to quench the reaction. The mixture was extracted with ethyl acetate (60 mL × 3 times), and the organic phases were combined and washed with saturated brine (60 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 100 mg of tert-butyl (3R)-3-[(2S)-1-(tert-butoxy)-3-(5-({[(3-[(2S)-3-(tert-butoxy))-2-[(3R)-1-[(tert-butoxy)carbonyl]pyrrolidin-3-yl]-3-oxopropyl]-4-methoxyphenyl)methyl]amino}methyl)-2-methoxyphenyl)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate.

[1006] MS (ESI) M / Z: 852.6 [M+H] + .

[1007] Step F: Tert-butyl (3R)-3-[(2S)-1-(tert-butoxy)-3-(5-({[(3-[(2S)-3-(tert-butoxy)-2-[(3R)-1-[(tert-butoxy)carbonyl]pyrrolidin-3-yl]-3-oxopropyl]-4-methoxyphenyl)methyl]amino}methyl)-2-methoxyphenyl)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (32 mg, The reaction mixture was stirred at 40°C for 16 hours.

[1008] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was added to ice water (100 mL) for quenching. The mixture was extracted with ethyl acetate (10 mL × 3 times), and the organic phases were combined and washed with saturated brine (10 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 30 mg of tert-butyl (3R)-3-[(2S)-1-(tert-butoxy)-3-(5-({[(7-[(2S)-3-(tert-butoxy))-2-[(3R)-1-[(tert-butoxy)carbonyl]pyrrolidin-3-yl]-3-oxopropyl]-2,3-dihydro-1,4-benzodioxin-5-yl)methyl][(3-[(2S)-3-(tert-butoxy)-2-[(3R)-1-[(tert-butoxy)carbonyl]pyrrolidin-3-yl]-3-oxopropyl]-4-methoxyphenyl)methyl]amino}methyl)-2-methoxyphenyl)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate.

[1009] MS (ESI) M / Z: 599.4 [(M-100) / 2+H] + .

[1010] Step G: Tert-butyl (3R)-3-[(2S)-1-(tert-butoxy)-3-(5-({[(7-[(2S)-3-(tert-butoxy))-2-[(3R)-1-[(tert-butoxy)carbonyl]pyrrolidin-3-yl]-3-oxopropyl]-2,3-dihydro-1,4-benzodioxin-5-yl)methyl][(3-[(2S)-3-(tert-butoxy)-2-[(3R)-1-[(tert-butoxy)carbonyl]pyrrolidin-3-yl]-3-oxopropyl]-4-methoxyphenyl)methyl]amino}methyl)-2-methoxyphenyl)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (25 mg, 0.02 mmol) was dissolved in 4 M hydrochloric acid in 1,4-dioxane (4 mL). The reaction system was then stirred for another 4 hours.

[1011] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was filtered, the filter cake was rinsed with dichloromethane (10 mL×2 times), the filter cake was collected, and concentrated under reduced pressure to obtain 16.2 mg of (S)-3-(5-((((7-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)-2,3-dihydrobenzo[b][1),4]dioxin-5-yl)methyl)(3-((R)-2-carboxy-2-((S)-pyrrolidin-3-yl)ethyl)-4-methoxybenzyl)amino)methyl)-2-methoxyphenyl)-2-((R)-pyrrolidin-3-yl)propanoic acid hydrochloride.

[1012] MS (ESI) M / Z: 830.4 [M+H] + .

[1013] 1 H NMR(400MHz,D2O)δ7.23-7.15(m,2H),7.06-6.94(m,4H),6.75(d,J=1.6Hz,1H),6 .49(d,J=1.6Hz,1H),4.41-4.26(s,2H),4.24-4.01(m,8H),3.81(s,6H),3.63-3. 49(m,3H),3.42-3.33(m,3H),3.26-3.14(m,3H),3.09-2.95(m,3H),3.92-2.82(m ,2H),2.78-2.60(m,7H),2.57-2.42(m,3H),2.20-2.04(m,3H),1.78-1.59(m,3H).

[1014] Example 133

[1015] (2S,2'S)-3,3'-(((3-(4-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)phenyl)cyclobutyl)azinediyl)bis(methylene)bis(3,1-phenylene))bis(2-(((R)-pyrrolidin-3-yl)propanoic acid

[1016] The synthesis of Example 133 was based on Example 132.

[1017] MS (ESI) M / Z: 751.5 [M+H] + .

[1018] 1 H NMR(400MHz,D2O)δ7.47-6.96(m,12H),4.30-4.09(m,4H),4.08-3.78(m,1H),3.62-3.49(m,3H),3.47-3.1 2(m,7H),3.09-2.96(m,3H),2.94-2.39(m,14H),2.37-2.22(m,1H),2.18-2.04(m,4H),1.80-1.61(m,3H).

[1019] Examples 274 & 275

[1020] (2S,2'S)-3,3'-(((((S)-5-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)-2,3-dihydrobenzofuran-3-yl)nitrogendiyl)bis(methylene)bis(3,1-phenylene))bis(2-((R)-pyrrolidin-3-yl)propanoic acid)

[1021] (2S,2'S)-3,3'-(((((R)-5-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)-2,3-dihydrobenzofuran-3-yl)azepinediyl)bis(methylene))bis(3,1-phenylene))bis(2-((R)-pyrrolidin-3-yl)propanoic acid)

[1022] It can also be prepared according to the following steps:

[1023] Reaction route:

[1024] Steps:

[1025] Step A: Dissolve 1-(2-hydroxy-5-methylphenyl)ethane-1-one (10 g, 66.67 mmol) and cuprous bromide (19.13 g, 133.34 mmol) in chloroform / ethyl acetate (196 mL / 196 mL) at 0°C under nitrogen. The reaction mixture was stirred at 100°C for 16 hours.

[1026] After LCMS monitoring showed the disappearance of the starting material, the reaction was filtered, the filter cake was rinsed with dichloromethane (80 mL x 3 times), and the filtrate was collected. Water (200 mL) was added to the filtrate to quench the mixture, and the mixture was extracted with dichloromethane (150 mL x 3 times). The organic phases were combined and washed with saturated brine (200 mL x 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 12 g of 2-bromo-1-(2-hydroxy-5-methylphenyl)ethan-1-one.

[1027] Step B: Dissolve 2-bromo-1-(2-hydroxy-5-methylphenyl)ethane-1-one (12 g, 52.6 mmol) and sodium acetate (8.6 g, 105.2 mmol) in N,N-dimethylformamide (263 mL) at room temperature under nitrogen. The reaction mixture was stirred at 50°C for 1 hour.

[1028] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was filtered, the filter cake was rinsed with ethyl acetate (200 mL x 2), and the filtrate was collected. Ice water (1 L) was added to the filtrate to quench it, and the mixture was extracted with ethyl acetate (200 mL x 3). The organic phases were combined and washed with saturated brine (200 mL x 2). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 3.2 g of 5-methylbenzofuran-3(2H)-one.

[1029] 1H NMR (400MHz, DMSO-d6) δ7.54(d,J=8.6Hz,1H),7.42(s,1H),7.18(d,J=8.4Hz,1H),4.78(s,2H),2.32(s,3H).

[1030] Step C: Dissolve 5-methylbenzofuran-3(2H)-one (3.2 g, 21.6 mmol), azobisisobutyronitrile (708 mg, 4.32 mmol), and N-bromosuccinimide (4.6 g, 25.9 mmol) in tetrachloromethane (100 mL) at room temperature under nitrogen. The reaction system is then stirred at 80°C for 8 hours.

[1031] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was added to ice water (500 mL) for quenching. The mixture was extracted with dichloromethane (200 mL × 3 times), and the organic phases were combined and washed with saturated brine (200 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 2.2 g of 5-(bromomethyl)benzofuran-3(2H)-one.

[1032] 1 H NMR (400MHz, DMSO-d6) δ7.81(d,J=8.8Hz,1H),7.74(s,1H),7.30(d,J=8.4Hz,1H),4.84(s,2H),4.80(s,2H)

[1033] Step D: Dissolve (R)-tert-butyl 3-(2-((S)-4-benzyl-2-oxooxazolidin-3-yl)-2-oxoethyl)pyrrolidine-1-carboxylate (3.4 g, 8.76 mmol) in dry tetrahydrofuran (3.5 mL) at -30°C. Then, slowly add 1M lithium bistrimethylsilylamide (12.3 mL, 12.3 mmol) dropwise to the above system and stir for 30 minutes. Then, slowly add a solution of 5-(bromomethyl)benzofuran-3(2H)-one (2.2 g, 9.64 mmol) in tetrahydrofuran (3.5 mL) dropwise and stir for 30 minutes. Then, warm to 0°C and continue stirring for 2 hours.

[1034] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was added to an ice-cold saturated aqueous ammonium chloride solution (50 mL) to quench the mixture. The mixture was extracted with ethyl acetate (50 mL × 3 times), and the organic phases were combined and washed with saturated brine (50 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 2.3 g of tert-butyl (R)-3-((S)-1-((S)-4-benzyl-2-oxooxazolidin-3-yl)-1-oxo-3-(3-oxo-2,3-dihydrobenzofuran-5-yl)propan-2-yl)pyrrolidine-1-carboxylate.

[1035] Step E: In an ice-water bath under nitrogen, tert-butyl (R)-3-((S)-1-((S)-4-benzyl-2-oxooxazolidin-3-yl)-1-oxo-3-(3-oxo-2,3-dihydrobenzofuran-5-yl)propan-2-yl)pyrrolidine-1-carboxylate (600 mg, 1.12 mmol), ammonium acetate (285 mg, 3.7 mmol), and sodium cyanoborohydride (117 mg, 1.85 mmol) were dissolved in isopropanol (9 mL). The reaction was stirred at 90°C for 3 hours.

[1036] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was added to ice water (50 mL) to quench the reaction. The mixed solution was extracted with ethyl acetate (20 mL × 3 times), and the organic phases were combined and washed with saturated brine (20 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 300 mg of (3R)-3-((2S)-3-(3-amino-2,3-dihydrobenzofuran-5-yl)-1-((S)-4-benzyl-2-oxooxazolidin-3-yl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester.

[1037] MS (ESI) M / Z: 558.2 [M+23] + .

[1038] Step F: At 0°C under nitrogen, tert-butyl (3R)-3-((2S)-3-(3-amino-2,3-dihydrobenzofuran-5-yl)-1-((S)-4-benzyl-2-oxooxazolidin-3-yl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (300 mg, 0.56 mmol) was dissolved in tetrahydrofuran (3 mL). Benzyloxycarbonyl succinimide (167 mg, 0.67 mmol) was then added to the solution. The reaction was stirred for 1 hour.

[1039] After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched with ice water (40 mL). The mixture was extracted with ethyl acetate (20 mL × 3 times), and the organic phases were combined and washed with saturated sodium chloride aqueous solution (30 mL × 2 times). The mixture was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 288 mg of tert-butyl (3R)-3-((2S)-1-((S)-4-benzyl-2-oxooxazolidin-3-yl)-3-(3-(((benzyloxy)carbonyl)amino)-2,3-dihydrobenzofuran-5-yl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate.

[1040] MS (ESI) M / Z: 692.2 [M+23] + .

[1041] Step G: At 0°C, tert-butyl (3R)-3-((2S)-1-((S)-4-benzyl-2-oxooxazolidin-3-yl)-3-(3-(((benzyloxy)carbonyl)amino)-2,3-dihydrobenzofuran-5-yl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (288 mg, 0.43 mmol) was dissolved in tetrahydrofuran (2.9 mL). A 33% aqueous solution of hydrogen peroxide (74 mg, 0.65 mmol) in water (0.65 mL) and a solution of lithium hydroxide monohydrate (27 mg, 0.65 mmol) in water (0.8 mL) were slowly added dropwise to the solution. The reaction was stirred for 3 hours.

[1042] After LCMS monitoring showed...

Claims

1. A compound represented by formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof: in, M is selected from R a1 , R a2 , R a3 and R a5 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl; R a4 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkenyl; or R a4 is-L4-T4; m1 is selected from 0, 1, 2 or 3; L1, L2, L3 and L4 are each independently selected from a bond, -O(CR b1 R b2 ) n1 -、-(CR b3 R b4 ) n2 -、-NR b5 (CR b6 R b7 ) n3 -、-S(CR b8 R b9 ) n4 -、-SO-、-SO2(CR b10 R b11 ) n5 -、-S(=O)(CR b12 R b13 ) n6 -、-CO(CR b14 R b15 ) n7 -, -S(=O)(=NH)-,-N=CR b16 -、-Se(CR b17 R b18 ) n8 -、C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, -OC 3-8 Cycloalkyl, -O-3-8 membered heterocycloalkyl, the C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, -OC 3-8 Cycloalkyl, -O-3-8 membered heterocycloalkyl is optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 is substituted by one or more substituents in a haloalkoxy group; R b1 , R b2 , R b3 , R b4 , R b5 , R b6 , R b7 , R b8 , R b9 , R b10 , R b11 , R b12 , R b13 , R b14 , R b15 , R b16 , R b17 and R b18 Each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl, -L4-T4; or, R on the same carbon atom b1 and R b2 Connect to form C 3-8 Cycloalkyl; or, R on the same carbon atom b3 and R b4 Connect to form C 3-8 Cycloalkyl; or, R on the same carbon atom b6 and R b7 Connect to form C 3-8 Cycloalkyl; or, R on the same carbon atom b8 and R b9 Connect to form C 3-8 Cycloalkyl; or, R on the same carbon atom b10 and R b11 Connect to form C 3-8 Cycloalkyl; n1, n2, n3, n4, n5, n6, n7 and n8 are each independently selected from 0, 1, 2, 3 or 4; T1, T2, T3 and T4 are each independently selected from the following structural fragments: Alternatively, -L3-T3 is hydrogen; Alternatively, -L2-T2 is hydrogen; M1 is selected from a bond, -(CR 2-1 R 2-2 ) p4 - or NR 2-3 ; R2, R 2-1 , R 2-2 , R 2-3 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Haloalkoxy; Or, R 2-1 and R 2-2 Connect to form C 3-6 Cycloalkyl, the C 3-6 The cycloalkyl group is optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 is substituted by one or more substituents in a haloalkoxy group; R3 and R4 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Haloalkoxy; Or, R 2-1 Connected with R3 to form C 3-6 Cycloalkyl; Alternatively, two R4 on adjacent carbon atoms are linked to form a C 3-6 Cycloalkyl; R1, R 1-1 , R 1-2 , R 1-3 , R 1-4 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, -SF5, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 is substituted by one or more substituents in a haloalkoxy group; Or, R 2-3 and R 1-1 Connect to form a 5-6 membered heteroaryl group; Or, R 1-2 and R 1-3 Connect to form C 5-8 Cycloalkenyl, 5-8 membered heterocycloalkenyl, phenyl, 5-6 membered heteroaryl, the C 5-8 Cycloalkenyl, 5-8 membered heterocycloalkenyl, phenyl, 5-6 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 is substituted by one or more substituents in a haloalkoxy group; Or, R 1-4 and R 1-3 Connect to form C 5-8 Cycloalkenyl, 5-8 membered heterocycloalkenyl, phenyl, 5-6 membered heteroaryl, the C 5-8 Cycloalkenyl, 5-8 membered heterocycloalkenyl, phenyl, 5-6 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 is substituted by one or more substituents in a haloalkoxy group; Or, R in T1 1-2 and R in T2 1-1 or R 1-2 Connection formation-O(CR c1 R c2 ) p1 -、-(CH2) p2 -、-NR c3 (CH2) p3 -; R c1 , R c2 and R c3 Each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl; p1, p2 and p3 are each independently selected from 0, 1, 2, 3 or 4; R5 is selected from -COOH, -CONHCN, -CONHOH, -CONHSO2CH3, -PO(OH)2, -SO2OH, Ring A is selected from C 3-8 Cycloalkyl; Ring B is selected from 5-6 membered heterocycloalkyl, 5-10 membered heteroaryl and 5-6 membered heterocycloalkenyl; Ring C is selected from C 6-10 Aryl, C 3-8 Cycloalkyl, 5-10 membered heteroaryl, C 3-8 Heterocycloalkenylphenyl, C 3-8 Cycloalkenylphenyl; Ring D is selected from C 6-10 Aryl or 5-10 membered heteroaryl; p4 is independently selected from 0, 1, 2 or 3; n is independently selected from 0 or 1; x is independently selected from 0, 1, 2 or 3; y is independently selected from 0, 1, 2 or 3; z is independently selected from 0, 1, 2 or 3.

2. The compound, stereoisomer or pharmaceutically acceptable salt thereof according to claim 1, characterized in that: M is selected from R a1 , R a2 and R a3 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Haloalkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl; R a4 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Haloalkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl; or R a4 is-L4-T4; Preferably, M is selected from 3. The compound, stereoisomer or pharmaceutically acceptable salt thereof according to claim 1 or 2, characterized in that: R b1 , R b2 , R b3 , R b4 , R b5 , R b6 , R b7 , R b8 , R b9 , R b10 , R b11 , R b12 , R b13 , R b14 , R b15 , R b16 , R b17 and R b18 Each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Haloalkoxy, C 3-6 Cycloalkyl; or, R on the same carbon atom b1 and R b2 Connect to form C 3-6 Cycloalkyl; or, R on the same carbon atom b3 and R b4 Connect to form C 3-6 Cycloalkyl; or, R on the same carbon atom b6 and R b7 Connect to form C 3-6 Cycloalkyl; or, R on the same carbon atom b8 and R b9 Connect to form C 3-6 Cycloalkyl; or, R on the same carbon atom b10 and R b11 Connect to form C 3-6 Cycloalkyl; Preferably, L1, L2, L3 and L4 are independently selected from -CH2-, a bond, -CH2CH2-, <h2 style=";text-align:left;direction:ltr">*-N(CH3)CH2CH2-、*-NHCH2CH2-、-NH-、*-NHCH2-、*-N(CH3)CH2-、-O-、-S-、-SO-、-SO2-、-S(=O)(=NH)-、*-OCH2-、*-CH2O-、*-CH2NH-、*-SCH2-、*-SO2CH2-、<h2 style=";text-align:left;direction:ltr"> *-OC(CH3)2-, *-OCH2CH2-,*-N(CH2-T4)CH2-, *-S(=O)CH2-、*-C(=O)CH2-、*-C(=O)-、 -CF2-, *-N=CH-, *-SeCH2-, -Se-, *-CH2CH2Se-, *-OCD2-, *-CD2-, where the * end is connected to M.

4. The compound, stereoisomer or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, characterized in that: L1 and L2 are selected from -CH2-; L3 is selected from *-OCH2-; wherein the * end is connected to M.

5. The compound, stereoisomer or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, characterized in that: R2, R 2-1 , R 2-2 , R 2-3 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Haloalkoxy; Preferably, R 2-1 and R 2-2 are each independently selected from hydrogen or fluorine; R 2-3 is selected from hydrogen; R2 is selected from hydrogen; Or, R 2-1 and R 2-2 Connect to form cyclopropyl, Or, R 2-3 and R 1-1 Connection Formation 6. The compound, stereoisomer or pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, characterized in that: R1, R 1-1 , R 1-2 , R 1-3 , R 1-4 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Haloalkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Haloalkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 is substituted by one or more substituents in a haloalkoxy group; Preferably, R1, R 1-1 are each independently selected from hydrogen, methyl, fluorine, chlorine, methoxy or deuterium; R 1-2 , R 1-3 , R 1-4 Each is independently selected from hydrogen, methyl, methoxy, chlorine, fluorine, -NHCH3, bromine, -CH2OH, -CH2OCH3, -SF5, -OCH(CH3)2, -NHCH(CH3)2, or deuterium; Or, R 1-2 and R 1-3 Connect to form C 5-8 Cycloalkenyl, 5-8 membered heterocycloalkenyl, phenyl, 5-6 membered heteroaryl, the C 5-8 Cycloalkenyl, 5-8 membered heterocycloalkenyl, phenyl, 5-6 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Preferably, R 1-2 and R 1-3 Connection Formation Or, R 1-4 and R 1-3 Connect to form C 5-8 Cycloalkenyl, 5-8 membered heterocycloalkenyl, phenyl, 5-6 membered heteroaryl, the C 5-8 Cycloalkenyl, 5-8 membered heterocycloalkenyl, phenyl, 5-6 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Preferably, R 1-4 and R 1-3 Connection Formation 7. The compound, stereoisomer or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, characterized in that: R3 and R4 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Haloalkoxy; Preferably, R3 is independently selected from hydrogen; R4 is independently selected from hydrogen or methyl; Or, R 2-1 Connected with R3 to form a cyclopropyl group; Alternatively, two R4 on adjacent carbon atoms are linked to form a cyclopropyl group.

8. The compound, stereoisomer or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, characterized in that: R c1 , R c2 and R c3 Each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Haloalkoxy, C 3-6 Cycloalkyl; Preferably, R in T1 1-2 and R in T2 1-1 or R 1-2 Connect to form -CH2CH2-, -CH2-, -NH-, -O-, -NHCH2-, -N(CH3)-, -N(CH2CH3)-, 9. The compound, stereoisomer or pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, characterized in that: Ring A is selected from C 4-6 Cycloalkyl, preferably cyclobutyl, more preferably 10. The compound, stereoisomer or pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, characterized in that: Ring B is selected from 11. The compound, stereoisomer or pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, characterized in that: Ring C is selected from phenyl, The * end is connected to L1, L2, L3 or L4.

12. The compound, stereoisomer or pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, characterized in that: Ring D is selected from phenyl, 5-10 heteroaryl, preferably selected from phenyl or 13. The compound, stereoisomer or pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, characterized in that T3 Among them, R 1-2 and R 1-3 Connected to form a C5-C6 heterocycloalkenyl group; preferably, the heteroatom in the C5-C6 heterocycloalkenyl group is oxygen; more preferably, the number of heteroatoms in the C5-C6 heterocycloalkenyl group is 2.

14. The compound, stereoisomer or pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, characterized in that: Structure fragment for T1 and T2 are T3 15. The compound, stereoisomer or pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, characterized in that: Structure fragment for T1 and T2 are 16. A compound, stereoisomer or pharmaceutically acceptable salt thereof, characterized in that: The compound is shown below:

17. A pharmaceutical composition comprising the compound, stereoisomer or pharmaceutically acceptable salt thereof according to any one of claims 1 to 16 and a pharmaceutically acceptable carrier.

18. Use of the compound, stereoisomer or pharmaceutically acceptable salt thereof according to any one of claims 1 to 16 or the pharmaceutical composition according to claim 17 in the preparation of a medicament for treating cardiovascular disease; the cardiovascular disease is atherosclerotic cardiovascular disease or hyperlipoproteinemia; the atherosclerotic cardiovascular disease is preferably coronary heart disease, coronary atherosclerosis, ischemic stroke, myocardial infarction, atherosclerotic renal vascular disease, non-infarct coronary artery disease.

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